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Lu Z, Yu L, Bai Y, Cui Y, Shi M, Li Z, Li X, Zhong X, Jin Y, Wei C. The potential mechanisms of reciprocal regulation of gut microbiota-liver immune signaling in metabolic dysfunction-associated steatohepatitis revealed in multi-omics analysis. mSystems 2025:e0051825. [PMID: 40492756 DOI: 10.1128/msystems.00518-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Accepted: 05/13/2025] [Indexed: 06/12/2025] Open
Abstract
As a commonly known aggressive liver-related manifestation within the spectrum of metabolic syndrome with a significant risk of progressing to cirrhosis and hepatocellular carcinoma, metabolic dysfunction-associated steatohepatitis (MASH) is closely intertwined with obesity, insulin resistance, and dyslipidemia. Although the gut microbiota is implicated in MASH progression, the underlying mechanisms require further investigation. In this study, we sought to combine the analysis of the liver transcriptome, circulating metabolome, and gut microbiota to investigate the potential molecular mechanisms underlying the reciprocal regulation between gut microbiota and liver immune signaling. We utilized a high-fat and methionine/choline-deficient diet (HFMCD)-induced MASH model in a db/db mouse. Following annotation analysis using KEGG and Metorigin, a comprehensive correlation analysis was conducted among these genes and specific metabolites (such as L-glutamine, isocitric acid, putrescine, pyroglutamic acid, rhamnose) and gut microbiota genera (Enteroccus and Romboutsia). The results revealed intricate interactions among the liver's immune microenvironment, the metabolome, and the gut microbiota. These interactions suggest a potential regulatory mechanism for metabolic disorders and immune responses.IMPORTANCEOur multi-omics analysis showed that the interactions between gut microbiota and liver immune responses mediated by the disorders in lipid, amino acid, and glucose metabolism are associated with activation of the JAK-STAT and NF-κB signaling pathway in MASH. The multi-omics analysis provides valuable insights into the interactions among microbiota, circulating metabolites, and immune signaling. These insights can be harnessed to enhance the management of MASH.
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Affiliation(s)
- Zhaoyang Lu
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ligen Yu
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yun Bai
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yifeng Cui
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Meixin Shi
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Zhitao Li
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiaoxue Li
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Xin Zhong
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ye Jin
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Can Wei
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang, China
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Nikparast A, Razavi M, Sohouli MH, Hekmatdoost A, Dehghan P, Tohidi M, Rouhani P, Asghari G. The association between dietary intake of branched-chain amino acids and the odds of nonalcoholic fatty liver disease among overweight and obese children and adolescents. J Diabetes Metab Disord 2025; 24:19. [PMID: 39712343 PMCID: PMC11659539 DOI: 10.1007/s40200-024-01516-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 11/08/2024] [Indexed: 12/24/2024]
Abstract
Objectives Dietary supplementation with branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, has shown potential benefits for the metabolic profile. However, emerging population-based studies suggest that BCAAs may mediate pathways related to cardiometabolic risk factors, possibly due to their involvement in the dysregulation of insulin metabolic pathways. This study aimed to investigate the association between BCAAs intake and the odds of nonalcoholic fatty liver disease (NAFLD) in children and adolescents with overweight and obesity. Methods This cross-sectional study encompassed individuals aged 6 to 18 years with WHO body mass index (BMI)-for-age z-score ≥ 1. NAFLD diagnosis was done using an ultrasonography scan of the liver and gastroenterologist confirmation. Dietary BCAAs intake was assessed using a validated 147-item food frequency questionnaire. Logistic regression models, adjusted for potential confounders, were used to estimate the odds ratios (OR) and 95% confidence interval (CI) of NAFLD across quartiles of BCAAs intake. Results A total of 505 (52.9% boys) with mean ± SD age and BMI-for-age-Z-score of 10.0 ± 2.3 and 2.70 ± 1.01, respectively, were enrolled. After adjusting for potential confounders, participants in the highest quartile of total dietary BCAAs (OR: 1.87;95%CI:1.06-3.28) and leucine (OR: 1.84;95%CI:1.03-3.29) intake had greater odds of developing NAFLD compared with those in the lowest quartile. There was no significant association between dietary valine and isoleucine intake and the odds of NAFLD. Conclusions The study findings suggest that increased dietary intake of BCAAs, particularly leucine, may have detrimental effects on the development of NAFLD.
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Affiliation(s)
- Ali Nikparast
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Razavi
- Growth and development research center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pooneh Dehghan
- Department of Imaging, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Tohidi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pejman Rouhani
- Pediatric Gastroenterology and Hepatology Research Center Pediatrics Centre of Excellence Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Golaleh Asghari
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Pérez-Díaz AJ, Ros-Madrid I, Martínez-Sánchez MA, Rico-Chazarra S, Oliva-Bolarín A, Balaguer-Román A, Fernández-Ruiz VE, Martínez CM, Yuste JE, Ferrer-Gómez M, Llamoza-Torres CJ, Frutos MD, Núñez-Sánchez MÁ, Ramos-Molina B. Alterations in hepatic amino acid metabolism related to MASLD in individuals with obesity. J Physiol Biochem 2025:10.1007/s13105-025-01086-7. [PMID: 40335876 DOI: 10.1007/s13105-025-01086-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 04/25/2025] [Indexed: 05/09/2025]
Abstract
Deregulation of amino acid (AA) metabolism has been reported in several pathological conditions, including metabolic diseases (e.g., obesity and diabetes), cardiovascular diseases, and cancer. However, the role of alterations in AA levels in chronic liver disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely unexplored. In this study we aimed to evaluate the hepatic AA composition in patients with different stages of MASLD, and their relationship with MASLD-related risk factors. A case-control study was conducted in 40 patients with obesity undergoing bariatric surgery at Virgen de la Arrixaca University Hospital (Murcia, Spain), where MASLD diagnosis was confirmed by histological analysis of liver biopsies, and hepatic AA levels were measured using ultra-performance liquid chromatography high-resolution time-of-flight mass spectrometry. Our results revealed that the hepatic AA profile was significantly altered in patients with MASLD. More specifically, comparison between MASLD patients revealed a significant increase in hepatic levels of arginine, glycine and cystine in MASH samples compared to steatotic livers. In addition, hepatic concentrations of arginine, lysine and cystine positively correlated with histopathological diagnosis and other MASLD-related parameters, including transaminases and CK-18 levels. These findings suggest that alterations in certain hepatic AA levels such as arginine, lysine, glycine and cystine in MASLD patients could have translational relevance in understanding the onset of this disease.
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Affiliation(s)
| | - Inmaculada Ros-Madrid
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - María A Martínez-Sánchez
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Sara Rico-Chazarra
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Alba Oliva-Bolarín
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Andrés Balaguer-Román
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Virginia E Fernández-Ruiz
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Carlos M Martínez
- Experimental Pathology Platform, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - José E Yuste
- Metabolomics Platform of CEBAS-CSIC, Campus Universitario de Espinardo, Murcia, Spain
| | - Mercedes Ferrer-Gómez
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Camilo J Llamoza-Torres
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- Division of Liver Diseases, Department of Gastroenterology and Hepatology, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - María D Frutos
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - María Á Núñez-Sánchez
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
- Biomedical Research Institute of Murcia (IMIB) Edificio LAIB, Carretera Buenavista s/n, Murcia, Spain.
| | - Bruno Ramos-Molina
- Obesity, Diabetes and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
- Biomedical Research Institute of Murcia (IMIB) Edificio LAIB, Carretera Buenavista s/n, Murcia, Spain.
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Chen C, Qi J, Zhang K, Meng J, Lu Y, Wang F, Zhu X. Metabolic Dysfunction-associated Steatotic Liver Disease Increases the Risk of Primary Open-Angle Glaucoma. Ophthalmol Glaucoma 2025; 8:266-274. [PMID: 39755370 DOI: 10.1016/j.ogla.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/14/2024] [Accepted: 12/20/2024] [Indexed: 01/06/2025]
Abstract
PURPOSE Liver disease is associated with a range of extrahepatic complications, which have recently been expanded to include ophthalmic conditions. However, evidence is lacking regarding its impact on primary open-angle glaucoma (POAG). This study aimed to investigate whether major liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), viral hepatitis, and liver fibrosis and cirrhosis, were associated with POAG. DESIGN A prospective study based on the UK Biobank cohort with a 2-sample Mendelian randomization (MR) analysis for inferring causality. PARTICIPANTS A total of 332 345 UK Biobank participants free of glaucoma recruited between 2006 and 2010. METHODS The exposures of interest were severe liver diseases defined as hospital admission, including MASLD, ALD, viral hepatitis, and liver fibrosis and cirrhosis. The Cox proportional hazard models were used with each liver disease treated as a time-varying exposure. The MR analysis was further conducted based on the genome-wide association studies of a histologically characterized cohort for MASLD (n = 19 264) and the International Glaucoma Genetics Consortium cohort for POAG (n = 216 257). MAIN OUTCOME MEASURES The risk of POAG estimated by hazard ratio (HR) and 95% confidence interval (CI) in observational analysis and odds ratio (OR) and 95% CI in MR analysis. RESULTS Severe MASLD was associated with a 45% increased risk of POAG (HR, 1.45; 95% CI, 1.12-1.87; P = 0.005), whereas no association was identified between ALD, viral hepatitis, or liver fibrosis and cirrhosis and incident POAG. Subgroup analysis showed that the risk of POAG in relation to MASLD was higher in individuals having more physical activity (HR, 1.53; 95% CI, 1.04-2.25 vs. HR, 1.39; 95% CI, 0.99-1.95, P for interaction = 0.033). Mendelian randomization analysis provided evidence that MASLD was causally associated with a greater risk of POAG (inverse-variance weighted model: OR, 1.035; 95% CI, 1.010-1.061; P = 0.005). CONCLUSIONS Severe MASLD was longitudinally associated with an increased risk of incident POAG, with MR analyses suggesting a potential causal link. These findings suggest that a POAG examination should be considered in the holistic management of MASLD and further underscore the impact of the liver on eye health. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any materials discussed in this article.
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Affiliation(s)
- Chao Chen
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Jiao Qi
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Keke Zhang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Jiaqi Meng
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Yi Lu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Fei Wang
- Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
| | - Xiangjia Zhu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
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5
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Bågenholm V, Nordlin KP, Pasquadibisceglie A, Belinskiy A, Holm CM, Hotiana HA, Gotfryd K, Delemotte L, Nour-Eldin HH, Pedersen PA, Gourdon P. Cryo-EM structure of the human monocarboxylate transporter 10. Structure 2025; 33:891-902.e4. [PMID: 40112803 DOI: 10.1016/j.str.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/31/2025] [Accepted: 03/19/2025] [Indexed: 03/22/2025]
Abstract
The monocarboxylate transporter (MCT) membrane protein family has 14 human members that perform key cellular functions, such as regulating metabolism. MCT8 and MCT10 have unique cargo specificity, transporting thyroid hormone and, in the case of MCT10, aromatic amino acids. Dysfunctional MCT8 causes the severe Allan-Herndon-Dudley syndrome, yet the (patho)physiology and function of MCT8 and MCT10 are not clearly understood, especially at a structural level. We present the cryoelectron microscopy (cryo-EM) structure of MCT10, displaying the classical major facilitator superfamily fold, caught in an inward-open configuration. Together with cargo docking models, the outward-open MCT10 AlphaFold model and validating functional analysis, cargo specificity and transport principles are proposed. These findings significantly enhance our understanding of the structure and function of MCTs, information that also may be valuable for the development of novel treatments against MCT-related disorders to address global challenges such as diabetes, obesity, and cancer.
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Affiliation(s)
- Viktoria Bågenholm
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Karl Patric Nordlin
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Andrea Pasquadibisceglie
- Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Solna, 17165 Stockholm, Sweden
| | - Andrey Belinskiy
- DynaMo Center, Department of Plant and Environmental Sciences, University of Copenhagen, 1871 Frederiksberg, Denmark
| | - Caroline Marcher Holm
- DynaMo Center, Department of Plant and Environmental Sciences, University of Copenhagen, 1871 Frederiksberg, Denmark
| | - Hajira Ahmed Hotiana
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Kamil Gotfryd
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lucie Delemotte
- Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Solna, 17165 Stockholm, Sweden
| | - Hussam Hassan Nour-Eldin
- DynaMo Center, Department of Plant and Environmental Sciences, University of Copenhagen, 1871 Frederiksberg, Denmark
| | | | - Pontus Gourdon
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
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Xiao M, Zhou N, Tian Z, Sun C. Endogenous Metabolites in Metabolic Diseases: Pathophysiologic Roles and Therapeutic Implications. J Nutr 2025:S0022-3166(25)00227-5. [PMID: 40250565 DOI: 10.1016/j.tjnut.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025] Open
Abstract
Breakthroughs in metabolomics technology have revealed the direct regulatory role of metabolites in physiology and disease. Recent data have highlighted the bioactive metabolites involved in the etiology and prevention and treatment of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Numerous studies reveal that endogenous metabolites biosynthesized by host organisms or gut microflora regulate metabolic responses and disorders. Lipids, amino acids, and bile acids, as endogenous metabolic modulators, regulate energy metabolism, insulin sensitivity, and immune response through multiple pathways, such as insulin signaling cascade, chemical modifications, and metabolite-macromolecule interactions. Furthermore, the gut microbial metabolites short-chain fatty acids, as signaling regulators have a variety of beneficial impacts in regulating energy metabolic homeostasis. In this review, we will summarize information about the roles of bioactive metabolites in the pathogenesis of many metabolic diseases. Furthermore, we discuss the potential value of metabolites in the promising preventive and therapeutic perspectives of human metabolic diseases.
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Affiliation(s)
- Mengjie Xiao
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Ning Zhou
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Zhen Tian
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
| | - Changhao Sun
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
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7
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Ma X, Bian W, Song W, Lu Y, Wang Z, Yao Z, Xuan Q. Metabolome profiling across liver lobes and metabolic shifts of the MASLD mice. GENES & NUTRITION 2025; 20:9. [PMID: 40240942 PMCID: PMC12001577 DOI: 10.1186/s12263-025-00768-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND The mammalian liver executes its vital functions through intricate hepatic biochemistry. However, the complexity of the liver metabolome and its dynamic alterations during metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly understood. METHODS We established progressive MASLD mouse models through high-fat diet (HFD) and high-fat/high-cholesterol (HFHC) dietary-feeding across multiple time points. Utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and lipidomics, we systematically mapped the metabolome atlas of the mouse liver across five anatomical segments during the progression of MASLD. RESULTS By integration of data from two assays, we structurally annotated 426 lipids and 118 polar metabolites. The temporal progression of HFD feeding (0, 8, and 16 weeks) resulted in gradual metabolic deterioration across various liver segments. In HFHC-fed mice, metabolic alterations surged sharply from 0 to 8 weeks, followed by moderate progression until 16 weeks in different liver segments. Elevated levels of glycerolipids and cholesteryl esters, along with fluctuating acylcarnitine and fatty acid levels across various liver segments, suggested impaired energy metabolism and disrupted fatty acid oxidation. As MASLD progresses, a shift in sphingolipid metabolism, linked to inflammation, was observed, accompanied by significant alterations in phospholipid turnover patterns. Additionally, amino acid profiles in the livers of HFD-fed and HFHC-fed mice were altered, potentially influencing the regulation of energy metabolism, inflammation, and oxidative stress. These metabolic changes in lipids and amino acids displayed segment-specific patterns, indicating varying sensitivities to inflammation and mitochondrial β-oxidation across different liver lobes. Notably, the left lateral lobe showed heightened sensitivity to metabolic disturbances during MASLD progression. CONCLUSION Our findings provided in-depth understanding in hepatic metabolites of MASLD, offering a comprehensive resource for further investigation.
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Affiliation(s)
- Xiaolin Ma
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Wenbo Bian
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Wenting Song
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Yitong Lu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Zhen Wang
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China.
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
| | - Zhenyu Yao
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China.
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
| | - Qiuhui Xuan
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, China.
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- "Chuangxin China" Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic Diseases, Jinan, Shandong, China.
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
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8
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Chakraborty S, Anand S, Numan M, Bhandari RK. Ancestral bisphenol A exposure led to non-alcoholic fatty liver disease and sex-specific alterations in proline and bile metabolism pathways in the liver. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2025; 44:958-972. [PMID: 39953842 PMCID: PMC11933882 DOI: 10.1093/etojnl/vgae081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 02/17/2025]
Abstract
Endocrine-disrupting chemicals can induce metabolic alterations, resulting in diseases such as obesity, diabetes, and fatty liver disease, which can be inherited by offspring inhabiting uncontaminated environments. Bisphenol A (BPA), a well-known endocrine disruptor, can induce endocrine disruption, leading to metabolic disorders in subsequent generations without further exposure to BPA via nongenetic transgenerational inheritance. Using medaka as an animal model, we reported that ancestral BPA exposure leads to transgenerational nonalcoholic fatty liver disease (NAFLD) in grandchildren four generations after the initial exposure. It is unclear if transgenerational NAFLD developed because ancestral BPA exposure differs from that developed due to direct and continuous BPA exposure because the transgenerational disease develops in the absence of the stressor. We induced transgenerational NAFLD in medaka with ancestral BPA exposure (10 µg/L) at the F0 generation and examined transcriptional and metabolomic alterations in the liver of the F4 generation fish that continued to develop NAFLD. To understand the etiology of NAFLD in unexposed generations, we performed nontargeted liquid chromatography-mass spectrometry-based metabolomic analysis in combination with bulk RNA sequencing and determined biomarkers, co-expressed gene networks, and sex-specific pathways triggered in the liver. An integrated analysis of metabolomic and transcriptional alterations revealed a positive association with the severity of the NAFLD disease phenotype. Females showed increased NAFLD severity and had metabolic disruption involving proline metabolism, tryptophan metabolism, and bile metabolism pathways. The present results provide the transcriptional and metabolomic underpinning of metabolic disruption caused by ancestral BPA exposure, providing avenues for further research to understand the development and progression of transgenerational NAFLD caused by ancestral bisphenol A exposure.
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Affiliation(s)
- Sourav Chakraborty
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
| | - Santosh Anand
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
| | - Muhammad Numan
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, United States
| | - Ramji Kumar Bhandari
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
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9
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Zhang L, Du Y, Li Y, Wang T, Pan Y, Xue X, Mu X, Qiu J, Qian Y. Mitochondrial mechanism of florfenicol-induced nonalcoholic fatty liver disease in zebrafish using multi-omics technology. JOURNAL OF HAZARDOUS MATERIALS 2025; 486:136958. [PMID: 39724715 DOI: 10.1016/j.jhazmat.2024.136958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/10/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
Florfenicol (FF), a third-generation chloramphenicol antibiotic widely used in food-producing animals, has become a "pseudopersistent" environmental contaminant, raising concerns about its potential ecological and human health impacts. However, its bioaccumulation behavior and hepatotoxic mechanisms remain poorly understood. This study aims to address these gaps with a 28-day exposure experiment in adult zebrafish at 0.05 and 0.5 mg/L FF. Multiomic analyses (metabolomics, lipidomics, and transcriptomics), combined with histological and mitochondrial function assessments, were employed. Higher bioaccumulation was observed at 0.05 mg/L, potentially due to metabolic saturation at higher concentrations. Histological analysis revealed significant hepatic steatosis (>5 % steatosis area), indicative of moderate nonalcoholic fatty liver disease (NAFLD). Multiomic data demonstrated global dysregulation in energy metabolism, including marked alterations in lipids (accumulation of toxic sphingolipids, excessive fatty acids, and acylglycerol), amino acids, tricarboxylic acid cycle intermediates, and nucleotides. Crucially, mitochondrial dysfunction was identified as a central mechanism, with impaired respiratory chain activities, adenosine triphosphate depletion, elevated reactive oxygen species, and oxidative stress promoting NAFLD progression. These findings highlight mitochondrial impairment and oxidative stress as key drivers of FF-induced hepatotoxicity, providing novel insights into its toxicological mechanisms and emphasizing the ecological risks posed by antibiotic pollution in aquatic systems.
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Affiliation(s)
- Lin Zhang
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing 100093, China
| | - Yang Du
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Yameng Li
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Tiancai Wang
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Yecan Pan
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Xiaofeng Xue
- Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing 100093, China
| | - Xiyan Mu
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Jing Qiu
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
| | - Yongzhong Qian
- Key Laboratory of Agri-food Quality and Safety of Ministry of Agriculture and Rural Affairs, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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10
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Du J, Shen M, Chen J, Yan H, Xu Z, Yang X, Yang B, Luo P, Ding K, Hu Y, He Q. The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications. Front Pharmacol 2025; 15:1510080. [PMID: 39850557 PMCID: PMC11754210 DOI: 10.3389/fphar.2024.1510080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/20/2024] [Indexed: 01/25/2025] Open
Abstract
Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.
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Affiliation(s)
- Jiangxia Du
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Minhui Shen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiajia Chen
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bo Yang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kefeng Ding
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuhuai Hu
- Yuhong Pharmaceutical Technology Co., Ltd., Hangzhou, Zhejiang, China
| | - Qiaojun He
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
- Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, China
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11
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Sadri H, Ghaffari MH, Sauerwein H, Schuchardt S, Martín-Tereso J, Doelman J, Daniel JB. Longitudinal characterization of the muscle metabolome in dairy cows during the transition from lactation cessation to lactation resumption. J Dairy Sci 2025; 108:1062-1077. [PMID: 39343201 DOI: 10.3168/jds.2024-25324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/05/2024] [Indexed: 10/01/2024]
Abstract
Skeletal muscle is vital in maintaining metabolic homeostasis and adapting to the physiological needs of pregnancy and lactation. Despite advancements in understanding metabolic changes in dairy cows around calving and early lactation, there are still gaps in our knowledge, especially concerning muscle metabolism and the changes associated with drying off. This study aimed to characterize the skeletal muscle metabolome in the context of the dietary and metabolic changes occurring during the transition from the cessation of lactation to the resumption of lactation in dairy cows. Twelve Holstein dairy cows housed in tiestalls were dried off 6 wk before the expected calving date. Cows were individually fed ad libitum TMR composed of grass silage, corn silage, and concentrate during lactation and of corn silage, barley straw, and concentrate during the dry period. The metabolome was characterized in skeletal muscle samples (M. longissimus dorsi) collected on wk -7 (9 d before dry-off), -5 (6 d after dry-off), and wk -1, and wk 1 relative to calving. The targeted metabolomics approach was conducted using the MxP Quant 500 kit (Biocrates Life Sciences AG) with liquid chromatography, flow injection, and electrospray ionization triple quadrupole mass spectrometry. Statistical analysis on the muscle metabolite data was performed using MetaboAnalyst 5.0, which allowed us to conduct various multivariate analyses such as principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), informative heat map generation, and hierarchical clustering. The statistical analysis revealed a clear separation between pregnancy (wk -7, -5, and -1) and postcalving (wk 1). Starting 5 wk before calving and continuing through the first week thereafter, the concentration of 3-methylhistidine (3-MH) in the muscle increased. This coincided with an increase in the concentrations of 11 AA (Phe, His, Tyr, Trp, Arg, Asn, Leu, Ile, Gly, Ser, and Thr) in the first week after calving, whereas Gln decreased. l-Arginine pathway metabolites (homoarginine, ornithine, citrulline, and asymmetric dimethylarginine), betaine, and sarcosine followed a similar pattern, increasing from wk -7 to -5, but decreasing from wk -1 to 1. The transition from pregnancy to lactation was associated with an increase in concentrations of the long-chain acylcarnitine species C16, C16:1, C18, and C18:1 in the muscle, whereas the concentrations of phosphatidylcholine and sphingomyelin in the muscle remained stable. The significant changes observed in the metabolome mainly concerned the AA and AA-related metabolites, indicating muscle protein breakdown in the first week after calving. The metabolites produced by the l-Arg pathway might contribute to regulating skeletal muscle mass and function in periparturient dairy cows. The elevated concentrations of long-chain acylcarnitine species in the muscle in the first week after calving suggest incomplete fatty acid oxidation, likely due to insufficient metabolic adaptation in response to the fatty acid load around the time of calving.
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Affiliation(s)
- H Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 5166616471 Tabriz, Iran; Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - M H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - H Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - S Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | | | - John Doelman
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands
| | - J B Daniel
- Trouw Nutrition R&D, 3800 AG, Amersfoort, the Netherlands.
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12
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Flam E, Haas JT, Staels B. Liver metabolism in human MASLD: A review of recent advancements using human tissue metabolomics. Atherosclerosis 2025; 400:119054. [PMID: 39586140 DOI: 10.1016/j.atherosclerosis.2024.119054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/04/2024] [Accepted: 11/08/2024] [Indexed: 11/27/2024]
Abstract
Global incidence of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is on the rise while treatments remain elusive. MASLD is a disease of dysregulated systemic and hepatic metabolism. Current understanding of disease pathophysiology as it relates to metabolome changes largely comes from studies on animal models and human plasma. However, human tissue data are crucial for transitioning from mechanisms to clinical therapies. The close relationship between MASLD and comorbidities like obesity, type 2 diabetes and dyslipidemia make it difficult to determine the contribution from liver disease itself. Here, we review recent metabolomics studies in liver tissue from human MASLD patients, which have predominately focused on lipid metabolism, but also include bile acid, tricarboxylic acid (TCA) cycle, and branched chain amino acid (BCAA) metabolism. Several clinical trials are underway to target various of these lipid-related pathways in MASLD. Although only the β-selective thyroid hormone receptor agonist resmetirom has so far been approved for use, many metabolism-targeting pharmaceuticals show promising results for halting disease progression, if not promoting outright reversal. Ultimately, the scarcity of human tissue data and the variability of confounding factors, like obesity, within and between cohorts are impediments to the pathophysiological understanding required for efficient development of metabolic treatments.
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Affiliation(s)
- Emily Flam
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Joel T Haas
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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13
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Verma A, Rishabh M, Mathiyazhagan N, Ahirwar SS, Mukherjee S, Kotnis A. Metabolic Derangement in Non-Alcoholic Fatty Liver Disease: Opportunities for Early Diagnostic and Prognostic Markers. Curr Mol Med 2025; 25:269-277. [PMID: 38409703 DOI: 10.2174/0115665240269082240213115711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 02/28/2024]
Abstract
Non-alcoholic fatty liver disease is a globally prevalent disorder that can rapidly progress if not detected early. Currently, no accepted markers exist for early diagnosis and prognosis of NAFLD. This review describes derangement in major metabolic pathways of lipid, carbohydrate, and amino acids in NAFLD. It suggests that measuring levels of thrombospondin, TyG index, asymmetric dimethylarginine, LAL-A, GLP-1, FGF-21, and GSG index are potential markers for early diagnosis of NAFLD. A single marker may not indicate early NAFLD, and further large-scale studies on correlating levels of Thrombospondin-2, triglyceride-glucose index, and FGF-21 with NAFLD are warranted.
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Affiliation(s)
- Abhinav Verma
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, India
| | - Mittal Rishabh
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, India
| | | | - Sonu Singh Ahirwar
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, India
| | - Ashwin Kotnis
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, India
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14
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Tan EY, Muthiah MD, Sanyal AJ. Metabolomics at the cutting edge of risk prediction of MASLD. Cell Rep Med 2024; 5:101853. [PMID: 39657668 PMCID: PMC11722125 DOI: 10.1016/j.xcrm.2024.101853] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/12/2024] [Accepted: 11/14/2024] [Indexed: 12/12/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health threat globally. Management of patients afflicted with MASLD and research in this domain are limited by the lack of robust well-established non-invasive biomarkers for diagnosis, prognostication, and monitoring. The circulating metabolome reflects both the systemic metabo-inflammatory milieu and changes in the liver in affected individuals. In this review we summarize the available literature on changes in the different components of the metabolome in MASLD with a focus on changes that are linked to the presence of underlying steatohepatitis, severity of disease activity, and fibrosis stage. We further summarize the existing literature around biomarker panels that are derived from interrogation of the metabolome. Their relevance to disease biology and utility in practice are also discussed. We further highlight potential direction for future studies particularly to ensure they are fit for purpose and suitable for widespread use.
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Affiliation(s)
- En Ying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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15
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Zhang Y, Qiu J, Sun S, Fang X. Altered amino acid levels in young hypopituitarism: impact of NAFLD and insulin resistance. Amino Acids 2024; 56:65. [PMID: 39580591 PMCID: PMC11585508 DOI: 10.1007/s00726-024-03429-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
Elevated concentrations of amino acids (AAs) are commonly observed in patients with nonalcoholic fatty liver disease (NAFLD). Individuals with hypopituitarism (HP) are at a heightened risk of developing NAFLD due to factors such as visceral obesity, increased insulin resistance (IR), and disturbances in lipid metabolism. However, the changes in AAs concentrations associated with HP remain poorly understood. Therefore, our study aimed to investigate whether individuals with HP, who were not receiving growth hormone replacement therapy (GHRT), exhibited altered AAs compared to controls (CTs), and whether these AAs were associated with IR, the presence of NAFLD, and the Metabolic Syndrome (MetS) score. The AAs profiles of 133 young males with HP (age: 24.5 ± 5.9; 57 with NAFLD and 76 without NAFLD) and 90 age and BMI-matched CTs were analyzed using untargeted metabolomics. The results revealed that most AAs were found to be elevated in subjects with HPs compared to CTs. Glutamate, glutamine, norleucine, and branched-chain amino acids (BCAAs) (leucine and valine) were correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), with glutamate and norleucine showing independent linkage. Glutamate and proline levels were specifically associated with MetS score, while alanine and proline linked to NAFLD. Given that elevated glutamate and BCAAs levels have higher prevalence of NAFLD, we hypothesized that the changes in AAs observed in HPs may be attributed to the impact of NAFLD and IR.
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Affiliation(s)
- Yuwen Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiting Qiu
- Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shouyue Sun
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Xuqian Fang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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16
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Lin KH, Vilar-Gomez E, Corey KE, Connelly MA, Gupta SK, Lake JE, Chalasani N, Gawrieh S. MASLD in persons with HIV is associated with high cardiometabolic risk as evidenced by altered advanced lipoprotein profiles and targeted metabolomics. Lipids Health Dis 2024; 23:339. [PMID: 39420356 PMCID: PMC11484191 DOI: 10.1186/s12944-024-02317-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles. METHODS This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters. RESULTS Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use. CONCLUSIONS MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.
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Affiliation(s)
- Kung-Hung Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, Indianapolis, IN, 46202, USA
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, Indianapolis, IN, 46202, USA
| | - Kathleen E Corey
- Division of Gastroenterology, Department of Medicine, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Samir K Gupta
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jordan E Lake
- Division of Infectious Diseases, Department of Medicine, UTHealth Science Center at Houston, Houston, TX, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, Indianapolis, IN, 46202, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, Indianapolis, IN, 46202, USA.
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17
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Maruszczak K, Koren P, Radzikowski K, Pixner T, Suppli MP, Wewer Albrechtsen NJ, Weghuber D, Torbahn G. Glucagon, Metabolic Dysfunction-Associated Steatotic Liver Disease and Amino Acids in Humans and Animals without Diabetes Mellitus-An Evidence Map. Life (Basel) 2024; 14:1292. [PMID: 39459592 PMCID: PMC11509797 DOI: 10.3390/life14101292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/15/2024] [Accepted: 09/18/2024] [Indexed: 10/28/2024] Open
Abstract
INTRODUCTION Health systems are confronted with not only the growing worldwide childhood obesity epidemic but also associated comorbidities. These subsequently cause variations in distinct metabolic pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this evidence map is to systematically evaluate the evidence and to identify research gaps on glucagon-induced amino acid (AA) turnover and its metabolic interaction with MASLD. METHODOLOGY A systematic literature search was conducted up to April 2023 in three electronic databases. Studies were required to include at least two of the main research areas, glucagon, AA metabolism and MASLD. Two independent reviewers screened titles and abstracts according to prespecified eligibility criteria, as well as full-text articles. Results are summarized in tables stratified by human and animal studies and study population age. RESULTS Thirty-four references were ultimately included. The publication years dated back to 1965 showed a great increase from 2012 to 2023. In total, there were 19 animal studies and 15 human studies. Among the human studies, except for two studies in adolescents, all the studies were conducted in adults. In human studies, the methods used to evaluate metabolic changes differed among hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests. Thirteen studies focused on the metabolic effects of MASLD, while only two studies explored the interaction between MASLD, glucagon and AA metabolism in humans. The other 19 studies focused on metabolomics, beta cell function or just one topic of a research area and not on interactions between one another. CONCLUSION Research on the interaction between MASLD, glucagon and AA metabolism in humans is sparse and complete lacking in pediatrics. Furthermore, longitudinal studies with a focus on hyperglucagonemia independent of diabetes but related to MASLD present an unambiguous research gap.
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Affiliation(s)
- Katharina Maruszczak
- Department of Pediatrics, University Hospital Salzburg, Division of Gastroenterology, Hepatology and Nutrition, Paracelsus Medical University, 5020 Salzburg, Austria; (K.M.); (P.K.); (K.R.); (G.T.)
- Obesity Research Unit, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Pia Koren
- Department of Pediatrics, University Hospital Salzburg, Division of Gastroenterology, Hepatology and Nutrition, Paracelsus Medical University, 5020 Salzburg, Austria; (K.M.); (P.K.); (K.R.); (G.T.)
| | - Konrad Radzikowski
- Department of Pediatrics, University Hospital Salzburg, Division of Gastroenterology, Hepatology and Nutrition, Paracelsus Medical University, 5020 Salzburg, Austria; (K.M.); (P.K.); (K.R.); (G.T.)
| | - Thomas Pixner
- Obesity Research Unit, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria;
- Department of Pediatric and Adolescent Medicine, Salzkammergutklinikum Voecklabruck, 4864 Voecklabruck, Austria
| | - Malte Palm Suppli
- Department of Clinical Biochemistry, Copenhagen University Hospital—Bispebjerg, 2400 Copenhagen, Denmark;
| | | | - Daniel Weghuber
- Department of Pediatrics, University Hospital Salzburg, Division of Gastroenterology, Hepatology and Nutrition, Paracelsus Medical University, 5020 Salzburg, Austria; (K.M.); (P.K.); (K.R.); (G.T.)
- Obesity Research Unit, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Gabriel Torbahn
- Department of Pediatrics, University Hospital Salzburg, Division of Gastroenterology, Hepatology and Nutrition, Paracelsus Medical University, 5020 Salzburg, Austria; (K.M.); (P.K.); (K.R.); (G.T.)
- Obesity Research Unit, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria;
- Department of Pediatrics, Paracelsus Medical University, Klinikum Nürnberg, Universitätsklinik der Paracelsus Medizinischen Privatuniversität Nürnberg, 90471 Nuremberg, Germany
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18
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Yang C, Zhou D, Yu H, Chen Y, Lin H, Wu H, Deng C. Multichannel Nanogenerator-Driven Collaborative Metabolic Fingerprint Diagnostic Strategy for Early Screening and Risk Evaluation of Nonalcoholic Fatty Liver Disease. Anal Chem 2024; 96:10841-10850. [PMID: 38889297 DOI: 10.1021/acs.analchem.4c02369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD), along with its progressive forms nonalcoholic steatohepatitis (NASH) and NASH fibrosis, has emerged as a global health crisis. However, the absence of robust screening and risk evaluation tools contributes to the underdiagnosis of NAFLD. Herein, we reported a multichannel nanogenerator-assisted laser desorption/ionization mass spectrometry (LDI-MS) platform for early screening and risk evaluation of NAFLD. Specifically, titanium oxide nanosheets (TiNS) and covalent-organic framework nanosheets (COFNS) were employed as nanogenerators with excellent optical properties and exhibited efficient desorption/ionization during the LDI-MS process. Only ∼0.025 μL of serum without pretreatments and separation, serum metabolic fingerprints (SMFs) can be extracted within seconds. Notably, integrated SMFs from TiNS and COFNS significantly improved diagnostic performance and achieved the area under the curve (AUC) values of 1.000 with 100% sensitivity and 100% specificity for the validation sets of global diagnosis, early diagnosis, high-risk NASH, and NASH fibrosis evaluation. Additionally, four biomarker panels were identified, and their diagnostic AUC values were more than 0.944. Ultimately, key metabolic pathways indicating the change from simple NAFLD to high-risk NASH and NASH fibrosis were uncovered. This work provided a noninvasive and high-throughput screening and risk evaluation strategy for NAFLD healthcare management, thus contributing to the precise treatment of the NALFD.
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Affiliation(s)
- Chenjie Yang
- Department of Chemistry, Fudan University, Shanghai 200433, China
| | - Da Zhou
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hailong Yu
- Department of Chemistry, Fudan University, Shanghai 200433, China
| | - Yijie Chen
- Department of Chemistry, Fudan University, Shanghai 200433, China
| | - Hairu Lin
- Department of Chemistry, Fudan University, Shanghai 200433, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chunhui Deng
- Department of Chemistry, Fudan University, Shanghai 200433, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
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19
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Boutari C, Stefanakis K, Simati S, Guatibonza-García V, Valenzuela-Vallejo L, Anastasiou IA, Connelly MA, Kokkinos A, Mantzoros CS. Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity. Cardiovasc Diabetol 2024; 23:174. [PMID: 38762719 PMCID: PMC11102634 DOI: 10.1186/s12933-024-02264-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/03/2024] [Indexed: 05/20/2024] Open
Abstract
BACKGROUND Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.
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Affiliation(s)
- Chrysoula Boutari
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, SL418, Boston, MA, 02215, USA
| | - Konstantinos Stefanakis
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, SL418, Boston, MA, 02215, USA
| | - Stamatia Simati
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Valentina Guatibonza-García
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, SL418, Boston, MA, 02215, USA
| | - Laura Valenzuela-Vallejo
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, SL418, Boston, MA, 02215, USA
| | - Ioanna A Anastasiou
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | | | - Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, SL418, Boston, MA, 02215, USA.
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, 02218, USA.
- Department of Medicine, Boston VA Healthcare System, Boston, MA, 02130, USA.
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20
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Tinkov AA, Korobeinikova TV, Morozova GD, Aschner M, Mak DV, Santamaria A, Rocha JBT, Sotnikova TI, Tazina SI, Skalny AV. Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women. J Trace Elem Med Biol 2024; 83:127397. [PMID: 38290269 DOI: 10.1016/j.jtemb.2024.127397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/29/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024]
Abstract
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
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Affiliation(s)
- Alexey A Tinkov
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia.
| | - Tatiana V Korobeinikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Galina D Morozova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 10461 Bronx, NY, USA
| | - Daria V Mak
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Abel Santamaria
- Faculty of Sciencies, National Autonomous University of Mexico, 04510 Mexico City, Mexico
| | - Joao B T Rocha
- Departamento de Bioquímica e Biologia Molecular, CCNE, Universidade Federal de Santa Maria, Santa Maria 97105-900 RS, Brazil
| | - Tatiana I Sotnikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Serafima Ia Tazina
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Anatoly V Skalny
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
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21
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Baciu C, Ghosh S, Naimimohasses S, Rahmani A, Pasini E, Naghibzadeh M, Azhie A, Bhat M. Harnessing Metabolites as Serum Biomarkers for Liver Graft Pathology Prediction Using Machine Learning. Metabolites 2024; 14:254. [PMID: 38786731 PMCID: PMC11122840 DOI: 10.3390/metabo14050254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024] Open
Abstract
Graft injury affects over 50% of liver transplant (LT) recipients, but non-invasive biomarkers to diagnose and guide treatment are currently limited. We aimed to develop a biomarker of graft injury by integrating serum metabolomic profiles with clinical variables. Serum from 55 LT recipients with biopsy confirmed metabolic dysfunction-associated steatohepatitis (MASH), T-cell mediated rejection (TCMR) and biliary complications was collected and processed using a combination of LC-MS/MS assay. The metabolomic profiles were integrated with clinical information using a multi-class Machine Learning (ML) classifier. The model's efficacy was assessed through the Out-of-Bag (OOB) error estimate evaluation. Our ML model yielded an overall accuracy of 79.66% with an OOB estimate of the error rate at 19.75%. The model exhibited a maximum ability to distinguish MASH, with an OOB error estimate of 7.4% compared to 22.2% for biliary and 29.6% for TCMR. The metabolites serine and serotonin emerged as the topmost predictors. When predicting binary outcomes using three models: Biliary (biliary vs. rest), MASH (MASH vs. rest) and TCMR (TCMR vs. rest); the AUCs were 0.882, 0.972 and 0.896, respectively. Our ML tool integrating serum metabolites with clinical variables shows promise as a non-invasive, multi-class serum biomarker of graft pathology.
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Affiliation(s)
| | | | | | | | | | | | | | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2C4, Canada; (C.B.); (S.G.); (S.N.); (A.R.); (E.P.); (M.N.); (A.A.)
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22
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Fotakis C, Amanatidou AI, Kafyra M, Andreou V, Kalafati IP, Zervou M, Dedoussis GV. Circulatory Metabolite Ratios as Indicators of Lifestyle Risk Factors Based on a Greek NAFLD Case-Control Study. Nutrients 2024; 16:1235. [PMID: 38674925 PMCID: PMC11055137 DOI: 10.3390/nu16081235] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/16/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
An ensemble of confounding factors, such as an unhealthy diet, obesity, physical inactivity, and smoking, have been linked to a lifestyle that increases one's susceptibility to chronic diseases and early mortality. The circulatory metabolome may provide a rational means of pinpointing the advent of metabolite variations that reflect an adherence to a lifestyle and are associated with the occurrence of chronic diseases. Data related to four major modifiable lifestyle factors, including adherence to the Mediterranean diet (estimated on MedDietScore), body mass index (BMI), smoking, and physical activity level (PAL), were used to create the lifestyle risk score (LS). The LS was further categorized into four groups, where a higher score group indicates a less healthy lifestyle. Drawing on this, we analyzed 223 NMR serum spectra, 89 MASLD patients and 134 controls; these were coupled to chemometrics to identify "key" features and understand the biological processes involved in specific lifestyles. The unsupervised analysis verified that lifestyle was the factor influencing the samples' differentiation, while the supervised analysis highlighted metabolic signatures. Τhe metabolic ratios of alanine/formic acid and leucine/formic acid, with AUROC > 0.8, may constitute discriminant indexes of lifestyle. On these grounds, this research contributed to understanding the impact of lifestyle on the circulatory metabolome and highlighted "prudent lifestyle" biomarkers.
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Affiliation(s)
- Charalambos Fotakis
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 11635 Athens, Greece; (C.F.); (V.A.)
| | - Athina I. Amanatidou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece; (A.I.A.); (M.K.); (I.P.K.)
| | - Maria Kafyra
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece; (A.I.A.); (M.K.); (I.P.K.)
| | - Vasiliki Andreou
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 11635 Athens, Greece; (C.F.); (V.A.)
| | - Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece; (A.I.A.); (M.K.); (I.P.K.)
| | - Maria Zervou
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 11635 Athens, Greece; (C.F.); (V.A.)
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece; (A.I.A.); (M.K.); (I.P.K.)
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23
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Zhang Y, Wang Y, Liao X, Liu T, Yang F, Yang K, Zhou Z, Fu Y, Fu T, Sysa A, Chen X, Shen Y, Lyu J, Zhao Q. Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress. Nutr Metab (Lond) 2024; 21:12. [PMID: 38459503 PMCID: PMC10924388 DOI: 10.1186/s12986-024-00784-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 02/06/2024] [Indexed: 03/10/2024] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.
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Affiliation(s)
- Yongjie Zhang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yangli Wang
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
- School of Public Health, Hangzhou Medical College, Hangzhou, China
| | - Xin Liao
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Tong Liu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Fengyuan Yang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Kaiqiang Yang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhuohua Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yinxu Fu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ting Fu
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Aliaksei Sysa
- Belarusian State University, ISEI BSU, Minsk, Republic of Belarus
| | - Xiandan Chen
- Belarusian State University, ISEI BSU, Minsk, Republic of Belarus
| | - Yao Shen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Jianxin Lyu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China.
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| | - Qiongya Zhao
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China.
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
- School of Public Health, Hangzhou Medical College, Hangzhou, China.
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24
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Tauriainen MM, Csader S, Lankinen M, Lo KK, Chen C, Lahtinen O, El-Nezamy H, Laakso M, Schwab U. PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids. Nutrients 2024; 16:261. [PMID: 38257154 PMCID: PMC10819939 DOI: 10.3390/nu16020261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/11/2023] [Accepted: 12/25/2023] [Indexed: 01/24/2024] Open
Abstract
The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.
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Affiliation(s)
- Milla-Maria Tauriainen
- Department of Medicine, Endoscopy Unit, Kuopio University Hospital, 70029 Kuopio, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Susanne Csader
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Maria Lankinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Olli Lahtinen
- Diagnostic Imaging Centre, Department of Clinical Radiology, Kuopio University Hospital, 70029 Kuopio, Finland;
| | - Hani El-Nezamy
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70211 Kuopio, Finland;
- Department of Medicine, Kuopio University Hospital, 70029 Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70029 Kuopio, Finland
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25
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Melander SA, Kayed A, Andreassen KV, Karsdal MA, Henriksen K. OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes. Eur J Pharmacol 2024; 962:176215. [PMID: 38056618 DOI: 10.1016/j.ejphar.2023.176215] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 12/08/2023]
Abstract
OBJECTIVE Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.
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Affiliation(s)
| | | | | | | | - Kim Henriksen
- Nordic Bioscience, 2730 Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
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26
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Li HJ, Wang YS, Wang YN, Liu AR, Su XH, Ma ZA, Wang LX, Zhang ZY, Lv SQ, Miao J, Cui HT. Mechanical study of alisol B 23-acetate on methionine and choline deficient diet-induced nonalcoholic steatohepatitis based on untargeted metabolomics. Biomed Chromatogr 2024; 38:e5763. [PMID: 37858975 DOI: 10.1002/bmc.5763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/21/2023] [Accepted: 10/03/2023] [Indexed: 10/21/2023]
Abstract
Alisol B 23-acetate (AB23A) has been demonstrated to have beneficial effects on nonalcoholic steatohepatitis (NASH). However, the mechanisms of AB23A on NASH remain unclear. This study aimed to investigate the mechanisms underlying the metabolic regulatory effects of AB23A on NASH. We used AB23A to treat mice with NASH, which was induced by a methionine and choline deficient (MCD) diet. We initially investigated therapeutic effect and resistance to oxidation and inflammation of AB23A on NASH. Subsequently, we performed untargeted metabolomic analyses and relative validation assessments to evaluate the metabolic regulatory effects of AB23A. AB23A reduced lipid accumulation, ameliorated oxidative stress and decreased pro-inflammatory cytokines in the liver. Untargeted metabolomic analysis found that AB23A altered the metabolites of liver. A total of 55 differential metabolites and three common changed pathways were screened among the control, model and AB23A treatment groups. Further tests validated the effects of AB23A on modulating common changed pathway-involved factors. AB23A treatment can ameliorate NASH by inhibiting oxidative stress and inflammation. The mechanism of AB23A on NASH may be related to the regulation of alanine, aspartate and glutamate metabolism, d-glutamine and d-glutamate metabolism, and arginine biosynthesis pathways.
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Affiliation(s)
- Hua-Jun Li
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Yuan-Song Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Ya-Nan Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Ai-Ru Liu
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Xiu-Hai Su
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Zi-Ang Ma
- Graduate School of Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Li-Xin Wang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Zhong-Yong Zhang
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Shu-Quan Lv
- Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, China
| | - Jing Miao
- Tianjin Second People's Hospital, Tianjin, China
| | - Huan-Tian Cui
- Yunnan University of Traditional Chinese Medicine, Kunming, China
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27
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Rix I, Johansen ML, Lund A, Suppli MP, Chabanova E, van Hall G, Holst JJ, Wewer Albrechtsen NJ, Kistorp C, Knop FK. Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease. Endocr Connect 2024; 13:e230161. [PMID: 37947763 PMCID: PMC10762555 DOI: 10.1530/ec-23-0161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 11/10/2023] [Indexed: 11/12/2023]
Abstract
Aims Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. Methods We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Results Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. Conclusion MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.
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Affiliation(s)
- Iben Rix
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Zealand Pharma A/S, Søborg, Denmark
| | - Marie L Johansen
- Department of Medicine, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Malte P Suppli
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Elizaveta Chabanova
- Department of Radiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Gerrit van Hall
- Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline Kistorp
- Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
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28
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Masson HO, Samoudi M, Robinson CM, Kuo CC, Weiss L, Shams Ud Doha K, Campos A, Tejwani V, Dahodwala H, Menard P, Voldborg BG, Robasky B, Sharfstein ST, Lewis NE. Inferring secretory and metabolic pathway activity from omic data with secCellFie. Metab Eng 2024; 81:273-285. [PMID: 38145748 PMCID: PMC11177574 DOI: 10.1016/j.ymben.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 11/29/2023] [Accepted: 12/14/2023] [Indexed: 12/27/2023]
Abstract
Understanding protein secretion has considerable importance in biotechnology and important implications in a broad range of normal and pathological conditions including development, immunology, and tissue function. While great progress has been made in studying individual proteins in the secretory pathway, measuring and quantifying mechanistic changes in the pathway's activity remains challenging due to the complexity of the biomolecular systems involved. Systems biology has begun to address this issue with the development of algorithmic tools for analyzing biological pathways; however most of these tools remain accessible only to experts in systems biology with extensive computational experience. Here, we expand upon the user-friendly CellFie tool which quantifies metabolic activity from omic data to include secretory pathway functions, allowing any scientist to infer properties of protein secretion from omic data. We demonstrate how the secretory expansion of CellFie (secCellFie) can help predict metabolic and secretory functions across diverse immune cells, hepatokine secretion in a cell model of NAFLD, and antibody production in Chinese Hamster Ovary cells.
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Affiliation(s)
- Helen O Masson
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
| | | | | | - Chih-Chung Kuo
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
| | - Linus Weiss
- Department of Biochemistry, Eberhard Karls University of Tübingen, Germany
| | - Km Shams Ud Doha
- Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Alex Campos
- Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Vijay Tejwani
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
| | - Hussain Dahodwala
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
| | - Patrice Menard
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - Bjorn G Voldborg
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark; National Biologics Facility, Technical University of Denmark, Lyngby, Denmark
| | | | - Susan T Sharfstein
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
| | - Nathan E Lewis
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA; Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
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29
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Iannone V, Babu AF, Lok J, Gómez-Gallego C, D'Auria G, Vazquez-Uribe R, Vaaben TH, Bongers M, Mikkonen S, Vaittinen M, Tikkanen I, Kettunen M, Klåvus A, Sehgal R, Kaminska D, Pihlajamaki J, Hanhineva K, El-Nezami H, Sommer MOA, Kolehmainen M. Changes in liver metabolic pathways demonstrate efficacy of the combined dietary and microbial therapeutic intervention in MASLD mouse model. Mol Metab 2023; 78:101823. [PMID: 37839774 PMCID: PMC10618820 DOI: 10.1016/j.molmet.2023.101823] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 10/17/2023] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD. METHODS MASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis. RESULTS After the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver. CONCLUSIONS These data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.
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Affiliation(s)
- Valeria Iannone
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Ambrin Farizah Babu
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland
| | - Johnson Lok
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Carlos Gómez-Gallego
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland.
| | - Giuseppe D'Auria
- Sequencing and Bioinformatics Service, Foundation for the Promotion of Health and Biomedical Research of Valencia Region, FISABIO, 46020 Valencia, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ruben Vazquez-Uribe
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Troels Holger Vaaben
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Mareike Bongers
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Santtu Mikkonen
- University Department of Technical Physics, University of Eastern Finland, 70211 Kuopio, Finland
| | - Maija Vaittinen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Ida Tikkanen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Mikko Kettunen
- Biomedical Imaging Unit, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland
| | - Anton Klåvus
- Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland
| | - Ratika Sehgal
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Dorota Kaminska
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, USA
| | - Jussi Pihlajamaki
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70210 Kuopio, Finland
| | - Kati Hanhineva
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland; Department of Life Technologies, Food Sciences Unit, University of Turku, 20014 Turku, Finland
| | - Hani El-Nezami
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; University of Hong Kong, Hong Kong SAR, Molecular and Cell Biology Research Area, School of Biological Sciences, Hong Kong, Hong Kong, China
| | - Morten Otto Alexander Sommer
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark.
| | - Marjukka Kolehmainen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
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30
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Zhao J, Zeng J, Zhu C, Li X, Liu D, Zhang J, Li F, Targher G, Fan JG. Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study. BMC Med 2023; 21:469. [PMID: 38017422 PMCID: PMC10685523 DOI: 10.1186/s12916-023-03185-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. METHODS We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. RESULTS We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13-1.81) and lower glutamine (OR = 0.83, 95% CI 0.73-0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. CONCLUSIONS Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.
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Affiliation(s)
- Jian Zhao
- The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
- Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China.
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
| | - Jing Zeng
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Cairong Zhu
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xuechao Li
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Dong Liu
- The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Jun Zhang
- The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
- Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China
| | - Fei Li
- The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
- Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China
- Department of Developmental and Behavioral Pediatric & Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Ospedale Sacro Cuore - Don Calabria, Negrar di Valpolicella, Italy
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China.
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31
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Csader S, Chen X, Leung H, Männistö V, Pentikäinen H, Tauriainen MM, Savonen K, El-Nezami H, Schwab U, Panagiotou G. Gut ecological networks reveal associations between bacteria, exercise, and clinical profile in non-alcoholic fatty liver disease patients. mSystems 2023; 8:e0022423. [PMID: 37606372 PMCID: PMC10654067 DOI: 10.1128/msystems.00224-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 07/15/2023] [Indexed: 08/23/2023] Open
Abstract
IMPORTANCE Our study is applying a community-based approach to examine the influence of exercise on gut microbiota (GM) and discover GM structures linked with NAFLD improvements during exercise. The majority of microbiome research has focused on finding specific species that may contribute to the development of human diseases. However, we believe that complex diseases, such as NAFLD, would be more efficiently treated using consortia of species, given that bacterial functionality is based not only on its own genetic information but also on the interaction with other microorganisms. Our results revealed that exercise significantly changes the GM interaction and that structural alterations can be linked with improvements in intrahepatic lipid content and metabolic functions. We believe that the identification of these characteristics in the GM enhances the development of exercise treatment for NAFLD and will attract general interest in this field.
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Affiliation(s)
- Susanne Csader
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Xiuqiang Chen
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
| | - Howell Leung
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
| | - Ville Männistö
- Departments of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | | | - Milla-Maria Tauriainen
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Departments of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Kai Savonen
- Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Hani El-Nezami
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- University of Hong Kong School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Ursula Schwab
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Gianni Panagiotou
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
- Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Zhang C, Sui Y, Liu S, Yang M. Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. EXPLORATION OF DIGESTIVE DISEASES 2023:246-275. [DOI: https:/doi.org/10.37349/edd.2023.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/05/2023] [Indexed: 11/27/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, Shanxi Province, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
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Rodrigues PM, Afonso MB, Simão AL, Islam T, Gaspar MM, O'Rourke CJ, Lewinska M, Andersen JB, Arretxe E, Alonso C, Santos-Laso Á, Izquierdo-Sanchez L, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Prip-Buus C, Banales JM, Rodrigues CMP, Castro RE. miR-21-5p promotes NASH-related hepatocarcinogenesis. Liver Int 2023; 43:2256-2274. [PMID: 37534739 DOI: 10.1111/liv.15682] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/03/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
BACKGROUND AND AIMS The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis. METHODS Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively. RESULTS In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis. CONCLUSIONS Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.
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Affiliation(s)
- Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Tawhidul Islam
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Colm J O'Rourke
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Monika Lewinska
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Laura Izquierdo-Sanchez
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raúl Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | | | - Carina Prip-Buus
- Université Paris Descartes UMR-S1016, Institut Cochin, Paris, France
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Duarte PRA, Franco RR, Vilela DD, Caixeta DC, de Souza AV, Deconte SR, Mendes-Rodrigues C, Fidale TM, Espindola FS, Teixeira RR, Resende ES. Effects of an L-Leucine-Rich Diet on Liver and Kidneys in a Doxorubicin Toxicity Model. Life (Basel) 2023; 13:1823. [PMID: 37763227 PMCID: PMC10532802 DOI: 10.3390/life13091823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/24/2023] [Accepted: 08/02/2023] [Indexed: 09/29/2023] Open
Abstract
Supplements and diets containing L-leucine, a branched-chain amino acid, have been considered beneficial for controlling oxidative stress and maintaining cardiac tissue in toxicity models using doxorubicin, a drug widely used in cancer treatment. However, there is a lack of studies in the literature that assess the effects of this diet on other organs and tissues, such as the liver and kidneys. Therefore, this study aimed to evaluate the effects of a leucine-rich diet on the liver and kidneys of healthy rats submitted to the doxorubicin toxicity model by analyzing biomarkers of oxidative stress and histological parameters. The animals were divided into four groups: naive, doxorubicin, L-leucine, and doxorubicin + L-leucine, and the diet was standardized with 5% L-leucine and a dose of 7.5 mg/kg of doxorubicin. We evaluated tissue injury parameters and biomarkers of oxidative stress, including enzymes, antioxidant profile, and oxidized molecules, in the liver and kidneys. Although some studies have indicated benefits of a diet rich in L-leucine for the muscle tissue of animals that received doxorubicin, our results showed that the liver was the most affected organ by the L-leucine-rich diet since the diet reduced its antioxidant defenses and increased the deposit of collagen and fat in the hepatic tissue. In the kidneys, the main alteration was the reduction in the number of glomeruli. These results contribute to the scientific literature and encourage further studies to evaluate the effects of an L-leucine-rich diet or its supplementation, alone or combined with doxorubicin using an animal model of cancer. Therefore, our study concludes that the leucine-rich diet itself was harmful and, when co-administered with doxorubicin, was not able to maintain the antioxidant defenses and tissue structure of the evaluated organs.
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Affiliation(s)
- Poliana Rodrigues Alves Duarte
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Rodrigo Rodrigues Franco
- Departamento de Medicina, Universidade Federal de Catalão, Catalão 75706-881, GO, Brazil;
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Danielle Diniz Vilela
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Douglas Carvalho Caixeta
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Adriele Vieira de Souza
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Simone Ramos Deconte
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Clesnan Mendes-Rodrigues
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
| | - Thiago Montes Fidale
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
- Departamento de Medicina, Universidade Federal de Catalão, Catalão 75706-881, GO, Brazil;
| | - Foued Salmen Espindola
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Renata Roland Teixeira
- Instituto de Biotecnologia, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (D.D.V.); (D.C.C.); (A.V.d.S.)
| | - Elmiro Santos Resende
- Faculdade de Medicina, Universidade Federal de Uberlândia, Uberlândia 38400-902, MG, Brazil; (P.R.A.D.); (S.R.D.); (C.M.-R.); (T.M.F.)
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Amanatidou AI, Mikropoulou EV, Amerikanou C, Milanovic M, Stojanoski S, Bjelan M, Cesarini L, Campolo J, Thanopoulou A, Banerjee R, Kurth MJ, Milic N, Medic-Stojanoska M, Trivella MG, Visvikis-Siest S, Gastaldelli A, Halabalaki M, Kaliora AC, Dedoussis GV, on behalf of the Mast4Health consortium. Plasma Amino Acids in NAFLD Patients with Obesity Are Associated with Steatosis and Fibrosis: Results from the MAST4HEALTH Study. Metabolites 2023; 13:959. [PMID: 37623902 PMCID: PMC10456787 DOI: 10.3390/metabo13080959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been linked to changes in amino acid (AA) levels. The objective of the current study was to examine the relationship between MRI parameters that reflect inflammation and fibrosis and plasma AA concentrations in NAFLD patients. Plasma AA levels of 97 NAFLD patients from the MAST4HEALTH study were quantified with liquid chromatography. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers, were measured. In total, subjects with a higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to subjects with lower PDFF. The concentrations of BCAAs (p-Value: 0.03), AAAs (p-Value: 0.039), L-valine (p-Value: 0.029), L-tyrosine (p-Value: 0.039) and L-isoleucine (p-Value: 0.032) were found to be significantly higher in the higher PDFF group compared to lower group. Plasma AA levels varied according to MRI-PDFF. Significant associations were also demonstrated between AAs and MRI-PDFF and MRI-cT1, showing the potential utility of circulating AAs as diagnostic markers of NAFLD.
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Affiliation(s)
- Athina I. Amanatidou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (C.A.); (G.V.D.)
| | - Eleni V. Mikropoulou
- Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece; (E.V.M.); (M.H.)
| | - Charalampia Amerikanou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (C.A.); (G.V.D.)
| | - Maja Milanovic
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia; (M.M.); (S.S.); (M.B.); (N.M.); (M.M.-S.)
| | - Stefan Stojanoski
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia; (M.M.); (S.S.); (M.B.); (N.M.); (M.M.-S.)
- Center for Diagnostic Imaging, Oncology Institute of Vojvodine, 21204 Sremska Kamenica, Serbia
| | - Mladen Bjelan
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia; (M.M.); (S.S.); (M.B.); (N.M.); (M.M.-S.)
| | - Lucia Cesarini
- Division of Hepatology and Gastroenterology, ASST Grande Ospedale Metropolitano, 20162 Milan, Italy;
| | - Jonica Campolo
- Institute of Clinical Physiology, CNR, 56124 Milan, Italy;
| | - Anastasia Thanopoulou
- Diabetes Center, 2nd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens, 15772 Athens, Greece;
| | | | - Mary Jo Kurth
- Clinical Studies Group, Randox Laboratories Ltd., Crumlin BT29 4RN, UK;
| | - Natasa Milic
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia; (M.M.); (S.S.); (M.B.); (N.M.); (M.M.-S.)
| | - Milica Medic-Stojanoska
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia; (M.M.); (S.S.); (M.B.); (N.M.); (M.M.-S.)
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia
| | - Maria Giovanna Trivella
- Institute of Clinical Physiology National Research Council, 56124 Pisa, Italy; (M.G.T.); (A.G.)
- ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy
| | - Sophie Visvikis-Siest
- INSERM UMR U1122, IGE-PCV, Faculté de Pharmacie, Université de Lorraine, 30 Rue Lionnois, 54000 Nancy, France;
| | - Amalia Gastaldelli
- Institute of Clinical Physiology National Research Council, 56124 Pisa, Italy; (M.G.T.); (A.G.)
| | - Maria Halabalaki
- Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece; (E.V.M.); (M.H.)
| | - Andriana C. Kaliora
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (C.A.); (G.V.D.)
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (C.A.); (G.V.D.)
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Roth Flach RJ, Bollinger E, Reyes AR, Laforest B, Kormos BL, Liu S, Reese MR, Martinez Alsina LA, Buzon L, Zhang Y, Bechle B, Rosado A, Sahasrabudhe PV, Knafels J, Bhattacharya SK, Omoto K, Stansfield JC, Hurley LD, Song L, Luo L, Breitkopf SB, Monetti M, Cunio T, Tierney B, Geoly FJ, Delmore J, Siddall CP, Xue L, Yip KN, Kalgutkar AS, Miller RA, Zhang BB, Filipski KJ. Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels. Nat Commun 2023; 14:4812. [PMID: 37558654 PMCID: PMC10412597 DOI: 10.1038/s41467-023-40536-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 07/25/2023] [Indexed: 08/11/2023] Open
Abstract
Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.
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Affiliation(s)
- Rachel J Roth Flach
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA.
| | - Eliza Bollinger
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Allan R Reyes
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Brigitte Laforest
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Bethany L Kormos
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Shenping Liu
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Matthew R Reese
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | | | - Leanne Buzon
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Yuan Zhang
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Bruce Bechle
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Amy Rosado
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | | | - John Knafels
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | | | - Kiyoyuki Omoto
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - John C Stansfield
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Liam D Hurley
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - LouJin Song
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Lina Luo
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | | | - Mara Monetti
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Teresa Cunio
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Brendan Tierney
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Frank J Geoly
- Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA
| | - Jake Delmore
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - C Parker Siddall
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Liang Xue
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Ka N Yip
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Amit S Kalgutkar
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Russell A Miller
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Bei B Zhang
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA
| | - Kevin J Filipski
- Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA.
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Zhang J, Yang Y, Wang Z, Zhang X, Zhang Y, Lin J, Du Y, Wang S, Si D, Bao J, Tian X. Integration of Metabolomics, Lipidomics, and Proteomics Reveals the Metabolic Characterization of Nonalcoholic Steatohepatitis. J Proteome Res 2023; 22:2577-2592. [PMID: 37403919 DOI: 10.1021/acs.jproteome.3c00009] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2023]
Abstract
Metabolic dysfunction is associated with nonalcoholic steatohepatitis (NASH) development. However, omics studies investigating metabolic changes in NASH patients are limited. In this study, metabolomics and lipidomics in plasma, as well as proteomics in the liver, were performed to characterize the metabolic profiles of NASH patients. Moreover, the accumulation of bile acids (BAs) in NASH patients prompted us to investigate the protective effect of cholestyramine on NASH. The liver expression of essential proteins involved in FA transport and lipid droplets was significantly elevated in patients with NASH. Furthermore, we observed a distinct lipidomic remodeling in patients with NASH. We also report a novel finding suggesting an increase in the expression of critical proteins responsible for glycolysis and the level of glycolytic output (pyruvic acid) in patients with NASH. Furthermore, the accumulation of branched chain amino acids, aromatic amino acids, purines, and BAs was observed in NASH patients. Similarly, a dramatic metabolic disorder was also observed in a NASH mouse model. Cholestyramine not only significantly alleviated liver steatosis and fibrosis but also reversed NASH-induced accumulation of BAs and steroid hormones. In conclusion, NASH patients were characterized by perturbations in FA uptake, lipid droplet formation, glycolysis, and accumulation of BAs and other metabolites.
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Affiliation(s)
- Ji Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Yiqin Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Zipeng Wang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xiaofen Zhang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yingfan Zhang
- College of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China
| | - Jiashuo Lin
- School of Medicine, Zhengzhou University, Zhengzhou 450052, China
| | - Yue Du
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Suhua Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | | | - Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
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38
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Leung H, Xiong L, Ni Y, Busch A, Bauer M, Press AT, Panagiotou G. Impaired flux of bile acids from the liver to the gut reveals microbiome-immune interactions associated with liver damage. NPJ Biofilms Microbiomes 2023; 9:35. [PMID: 37286586 DOI: 10.1038/s41522-023-00398-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 05/18/2023] [Indexed: 06/09/2023] Open
Abstract
Currently, there is evidence that alteration in the gut ecosystem contributes to the development of liver diseases, however, the complex mechanisms involved are still unclear. We induced cholestasis in mice by bile duct ligation (BDL), mirroring the phenotype of a bile duct obstruction, to understand how gut microbiota alterations caused by an impaired flow of bile acid to the gut contribute to the pathogenesis and progression of liver disease. We performed longitudinal stool, heart, and liver sampling using mice receiving BDL and controls receiving sham operation (ShamOP). Shotgun metagenomics profiling using fecal samples taken before and on day 1, day 3, and day 7 after surgery was performed, and the cytokines and clinical chemistry profiles from heart blood, as well as the liver bile acids profile, were measured. The BDL surgery reshaped the microbiome of mice, resulting in highly distinct characteristics compared to the ShamOP. Our analysis of the microbiome pathways and ECs revealed that BDL reduces the production of hepatoprotective compounds in the gut, such as biotin, spermidine, arginine, and ornithine, which were negatively associated with inflammatory cytokines (IL-6, IL-23, MCP-1). The reduction of the functional potential of the gut microbiota in producing those hepatoprotective compounds is associated with the decrease of beneficial bacteria species from Anaerotruncus, Blautia, Eubacterium, and Lachnoclostridium genera, as well as the increase of disease-associated bacteria e.g., Escherichia coli and Entercoccus faecalis. Our findings advances our knowledge of the gut microbiome-bile acids-liver triangle, which may serve as a potential therapeutic strategy for liver diseases.
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Affiliation(s)
- Howell Leung
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
| | - Ling Xiong
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany
| | - Yueqiong Ni
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany
| | - Anne Busch
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany
- Friedrich Schiller University, Theoretical Microbial Ecology, Institute of Microbiology, Faculty of Biological Sciences, Jena, Germany
| | - Michael Bauer
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany
| | - Adrian T Press
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Jena, Germany.
- Friedrich Schiller University, Medical Faculty, Jena, Germany.
| | - Gianni Panagiotou
- Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
- Friedrich Schiller University Jena, Institute of Microbiology, Faculty of Biological Sciences, Jena, Germany.
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39
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Dolce A, Della Torre S. Sex, Nutrition, and NAFLD: Relevance of Environmental Pollution. Nutrients 2023; 15:nu15102335. [PMID: 37242221 DOI: 10.3390/nu15102335] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and represents an increasing public health issue given the limited treatment options and its association with several other metabolic and inflammatory disorders. The epidemic, still growing prevalence of NAFLD worldwide cannot be merely explained by changes in diet and lifestyle that occurred in the last few decades, nor from their association with genetic and epigenetic risk factors. It is conceivable that environmental pollutants, which act as endocrine and metabolic disruptors, may contribute to the spreading of this pathology due to their ability to enter the food chain and be ingested through contaminated food and water. Given the strict interplay between nutrients and the regulation of hepatic metabolism and reproductive functions in females, pollutant-induced metabolic dysfunctions may be of particular relevance for the female liver, dampening sex differences in NAFLD prevalence. Dietary intake of environmental pollutants can be particularly detrimental during gestation, when endocrine-disrupting chemicals may interfere with the programming of liver metabolism, accounting for the developmental origin of NAFLD in offspring. This review summarizes cause-effect evidence between environmental pollutants and increased incidence of NAFLD and emphasizes the need for further studies in this field.
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Affiliation(s)
- Arianna Dolce
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| | - Sara Della Torre
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
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40
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Masson HO, Samoudi M, Robinson CM, Kuo CC, Weiss L, Doha KSU, Campos A, Tejwani V, Dahodwala H, Menard P, Voldborg BG, Sharfstein ST, Lewis NE. Inferring secretory and metabolic pathway activity from omic data with secCellFie. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.04.539316. [PMID: 37205389 PMCID: PMC10187314 DOI: 10.1101/2023.05.04.539316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Understanding protein secretion has considerable importance in the biotechnology industry and important implications in a broad range of normal and pathological conditions including development, immunology, and tissue function. While great progress has been made in studying individual proteins in the secretory pathway, measuring and quantifying mechanistic changes in the pathway's activity remains challenging due to the complexity of the biomolecular systems involved. Systems biology has begun to address this issue with the development of algorithmic tools for analyzing biological pathways; however most of these tools remain accessible only to experts in systems biology with extensive computational experience. Here, we expand upon the user-friendly CellFie tool which quantifies metabolic activity from omic data to include secretory pathway functions, allowing any scientist to infer protein secretion capabilities from omic data. We demonstrate how the secretory expansion of CellFie (secCellFie) can be used to predict metabolic and secretory functions across diverse immune cells, hepatokine secretion in a cell model of NAFLD, and antibody production in Chinese Hamster Ovary cells.
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Affiliation(s)
- Helen O. Masson
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
| | | | | | - Chih-Chung Kuo
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
| | - Linus Weiss
- Department of Biochemistry, Eberhard Karls University of Tübingen, Germany
| | - Km Shams Ud Doha
- Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Alex Campos
- Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Vijay Tejwani
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
| | - Hussain Dahodwala
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
- Present address: National Institute for Innovation in Manufacturing Biopharmaceuticals, Newark, Delaware, USA
| | - Patrice Menard
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - Bjorn G. Voldborg
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
- National Biologics Facility, Technical University of Denmark, Lyngby, Denmark
| | - Susan T. Sharfstein
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
| | - Nathan E. Lewis
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
- Department of Pediatrics, UC San Diego, La Jolla, CA, USA
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41
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Bjune MS, Lawrence-Archer L, Laupsa-Borge J, Sommersten CH, McCann A, Glastad RC, Johnston IG, Kern M, Blüher M, Mellgren G, Dankel SN. Metabolic role of the hepatic valine/3-hydroxyisobutyrate (3-HIB) pathway in fatty liver disease. EBioMedicine 2023; 91:104569. [PMID: 37084480 PMCID: PMC10148099 DOI: 10.1016/j.ebiom.2023.104569] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation. METHODS HIBCH mRNA in human liver biopsies ("Liver cohort") and plasma 3-HIB ("CARBFUNC" cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays. FINDINGS We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS. INTERPRETATION These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention. FUNDING Funding was provided by the Research Council of Norway (263124/F20), the University of Bergen, the Western Norway Health Authorities, Novo Nordisk Scandinavia AS, the Trond Mohn Foundation and the Norwegian Diabetes Association.
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Affiliation(s)
- Mona Synnøve Bjune
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
| | - Laurence Lawrence-Archer
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
| | - Johnny Laupsa-Borge
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Bevital AS, Bergen, Norway
| | - Cathrine Horn Sommersten
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | | | - Iain George Johnston
- Department of Mathematics, University of Bergen, Bergen, Norway; Computational Biology Unit, University of Bergen, Bergen, Norway
| | - Matthias Kern
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany; Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany; Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Gunnar Mellgren
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
| | - Simon N Dankel
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
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42
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Guo Y, Liu M, Liu X, Zheng M, Xu X, Liu X, Gong J, Liu H, Liu J. Metagenomic and Untargeted Metabolomic Analysis of the Effect of Sporisorium reilianum Polysaccharide on Improving Obesity. Foods 2023; 12:foods12081578. [PMID: 37107373 PMCID: PMC10137368 DOI: 10.3390/foods12081578] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/01/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Gut microbiota plays an important role in the pathophysiology of obesity. Fungal polysaccharide can improve obesity, but the potential mechanism needs further study. This experiment studied the potential mechanism of polysaccharides from Sporisorium reilianum (SRP) to improve obesity in male Sprague Dawley (SD) rats fed with a high-fat diet (HFD) using metagenomics and untargeted metabolomics. After 8 weeks of SRP (100, 200, and 400 mg/kg/day) intervention, we analyzed the related index of obesity, gut microbiota, and untargeted metabolomics of rats. The obesity and serum lipid levels of rats treated with SRP were reduced, and lipid accumulation in the liver and adipocyte hypertrophy was improved, especially in rats treated with a high dose of SRP. SRP improved the composition and function of gut microbiota in rats fed with a high-fat diet, and decreased the ratio of Firmicutes to Bacteroides at the phylum level. At the genus level, the abundance of Lactobacillus increased and that of Bacteroides decreased. At the species level, the abundance of Lactobacillus crispatus, Lactobacillus helveticus, and Lactobacillus acidophilus increased, while the abundance of Lactobacillus reuteri and Staphylococcus xylosus decreased. The function of gut microbiota mainly regulated lipid metabolism and amino acid metabolism. The untargeted metabolomics indicated that 36 metabolites were related to the anti-obesity effect of SRP. Furthermore, linoleic acid metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and the phenylalanine metabolism pathway played a role in improving obesity in those treated with SRP. The study results suggest that SRP significantly alleviated obesity via gut-microbiota-related metabolic pathways, and SRP could be used for the prevention and treatment of obesity.
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Affiliation(s)
- Yunlong Guo
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Meihong Liu
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
| | - Xin Liu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Mingzhu Zheng
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
| | - Xiuying Xu
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
| | - Xiaokang Liu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jiyu Gong
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Huimin Liu
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
| | - Jingsheng Liu
- National Engineering Research Center for Wheat and Corn Deep Processing, College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
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Elingaard-Larsen LO, Villumsen SO, Justesen L, Thuesen ACB, Kim M, Ali M, Danielsen ER, Legido-Quigley C, van Hall G, Hansen T, Ahluwalia TS, Vaag AA, Brøns C. Circulating Metabolomic and Lipidomic Signatures Identify a Type 2 Diabetes Risk Profile in Low-Birth-Weight Men with Non-Alcoholic Fatty Liver Disease. Nutrients 2023; 15:nu15071590. [PMID: 37049431 PMCID: PMC10096690 DOI: 10.3390/nu15071590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/09/2023] [Accepted: 03/15/2023] [Indexed: 03/28/2023] Open
Abstract
The extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.
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44
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Kim HY, Kim DJ, Lee HA, Cho JY, Kim W. Baseline Tyrosine Level Is Associated with Dynamic Changes in FAST Score in NAFLD Patients under Lifestyle Modification. Metabolites 2023; 13:metabo13030444. [PMID: 36984884 PMCID: PMC10058052 DOI: 10.3390/metabo13030444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Noninvasive risk stratification is a challenging issue in the management of patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to identify multiomics-based predictors of NAFLD progression, as assessed by changes in serial FibroScan-aspartate aminotransferase (FAST) scores during lifestyle modification. A total of 266 patients with available metabolomics and genotyping data were included. The follow-up sub-cohort included patients with paired laboratory and transient elastography results (n = 160). The baseline median FAST score was 0.37. The PNPLA3 rs738409 genotype was significantly associated with a FAST score > 0.35. Circulating metabolomics significantly associated with a FAST score > 0.35 included SM C24:0 (odds ratio [OR] = 0.642; 95% confidence interval [CI], 0.463-0.891), PC ae C40:6 (OR = 0.477; 95% CI, 0.340-0.669), lysoPC a C18:2 (OR = 0.570; 95% CI, 0.417-0.779), and tyrosine (OR = 2.743; 95% CI, 1.875-4.014). A combination of these metabolites and PNPLA3 genotype yielded a c-index = 0.948 for predicting a FAST score > 0.35. In the follow-up sub-cohort (median follow-up = 23.7 months), 47/76 patients (61.8%) with a baseline FAST score > 0.35 had a follow-up FAST score ≤ 0.35. An improved FAST score at follow-up was significantly associated with age, serum alanine aminotransferase, and tyrosine. In conclusion, baseline risk stratification in NAFLD patients may be assisted using a multiomics-based model. Particularly, patients with increased tyrosine may benefit from an earlier switch to pharmacologic approaches.
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Affiliation(s)
- Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea
| | - Da Jung Kim
- Metabolomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Republic of Korea
| | - Hye Ah Lee
- Clinical Trial Center, Ewha Womans University Medical Center, Seoul 07985, Republic of Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
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45
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Grzych G, Bernard L, Lestrelin R, Tailleux A, Staels B. [State of the art on the pathophysiology, diagnosis and treatment of non-alcoholic steatohepatitis (NASH)]. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:183-201. [PMID: 36126753 DOI: 10.1016/j.pharma.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/13/2022] [Indexed: 11/15/2022]
Abstract
NAFLD or non-alcoholic fatty liver disease is one of the complications of obesity and diabetes, the prevalence of which is increasing. The causes of the pathology and its development towards its severe form, NASH or non-alcoholic steatohepatitis, are multiple and still poorly understood. Many different pharmacological classes are being tested in clinical trials to treat NASH, but no pharmaceutical treatment is currently on the market. Moreover, the diagnosis of certainty is only possible by liver biopsy and histological analysis, an invasive procedure with high risk for the patient. It is therefore necessary to better understand the natural history of the disease in order to identify therapeutic targets, but also to identify markers for the diagnosis and monitoring of the disease using a blood sample, which will allow an improvement in patient management.
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Affiliation(s)
- G Grzych
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - L Bernard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - R Lestrelin
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - A Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - B Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
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Zhang L, Qiu J, Li Y, He L, Mao M, Wang T, Pan Y, Li Z, Mu X, Qian Y. Maternal transfer of florfenicol impacts development and disrupts metabolic pathways in F1 offspring zebrafish by destroying mitochondria. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 252:114597. [PMID: 36739738 DOI: 10.1016/j.ecoenv.2023.114597] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
Maternal exposure to antibiotics existing in the environment is a predisposing factor for developmental malformation with metabolic disorders in offspring. In this study, female zebrafish (3 months) were exposed to 0.05 mg/L and 0.5 mg/L florfenicol (FF) for 28 days. After pairing and spawning with healthy male fish, F1 embryos were collected and developed to 5 d post-fertilization (dpf) in clear water. And the adverse effects on the F1 generation were examined thoroughly. The fecundity of F0 female fish and the hatchability, mortality, and body length of F1 larvae significantly decreased in the treatment group. Meanwhile, multi-malformation types were found in the exposure group, including delayed yolk sac absorption, lack of swim bladder, and spinal curvature. Metabolomic and transcriptomic results revealed alterations in metabolism with dysregulation in tricarboxylase acid cycle, amino acid metabolism, and disordered lipid metabolism with elevated levels of glycerophospholipid and sphingolipid. Accompanying these metabolic derangements, decreased levels of ATP and disordered oxidative-redox state were observed. These results were consistent with the damaged mitochondrial membrane potential and respiratory chain function, suggesting that the developmental toxicity and perturbed metabolic signaling in the F1 generation were related to the mitochondrial injury after exposing F0 female zebrafish to FF. Our findings highlighted the potential toxicity of FF to offspring generations even though they were not directly exposed to environmental contaminants.
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Affiliation(s)
- Lin Zhang
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Jing Qiu
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Yameng Li
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Linjuan He
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Mingcai Mao
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Tiancai Wang
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Yecan Pan
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Zishu Li
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Xiyan Mu
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China
| | - Yongzhong Qian
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Key Laboratory of Agri-food Quality and Safety, Ministry of Agriculture and Rural Affairs, Beijing 100081, China.
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Gong M, Lu H, Li L, Feng M, Zou Z. Integration of transcriptomics and metabonomics revealed the protective effects of hemp seed oil against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in mice. Food Funct 2023; 14:2096-2111. [PMID: 36734470 DOI: 10.1039/d2fo03054c] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with few therapeutic options available currently. Hemp seed oil extracted from the seeds of hemp (Cannabis sativa L.) has significant nutritional and biological properties due to the unique composition of polyunsaturated fatty acids and various antioxidant compounds. However, little is known about the beneficial effects and molecular mechanisms of hemp seed oil on NASH. Here, the hepatoprotective effects of hemp seed oil on methionine-choline-deficient (MCD) diet-induced NASH in C57BL/6 mice were explored via integration of transcriptomics and metabolomics. Hemp seed oil could improve hepatic steatosis, inflammation and fibrosis in mice with MCD diet-induced NASH. In a nuclear magnetic resonance (NMR)-based metabonomic study, the hepatic and urinary metabolic profiles of mice supplemented with hemp seed oil showed a tendency to recover to healthy controls compared to those of NASH mice. Eight potential biomarkers associated with NASH in both liver tissue and urine were restored to near normal levels by administration of hemp seed oil. The proposed pathways were mainly involved in pyrimidine metabolism, one-carbon metabolism, amino acid metabolism, glycolysis and the tricarboxylic acid (TCA) cycle. Hepatic transcriptomics based on Illumina RNA-Seq sequencing showed that hemp seed oil exerted anti-NASH activities by regulating multiple signaling pathways, e.g., downregulation of the TNF signaling pathway, the IL-17 signaling pathway, the MAPK signaling pathway and the NF-κB signaling pathway, which played a pivotal role in the pathogenesis of NASH. In particular, integration of metabonomic and transcriptomic results suggested that hemp seed oil could attenuate NASH-related liver fibrosis by inhibition of glutaminolysis. These results provided new insights into the hepatoprotective effects of hemp seed oil against MCD diet-induced NASH and hemp seed oil might have potential as an effective therapy for NASH.
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Affiliation(s)
- Mengjuan Gong
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Hailong Lu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Lixi Li
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Meiqi Feng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhongjie Zou
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Plasma Metabolite Signatures in Male Carriers of Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease. Metabolites 2023; 13:metabo13020267. [PMID: 36837886 PMCID: PMC9964056 DOI: 10.3390/metabo13020267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/01/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Both genetic and non-genetic factors are important in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to identify novel metabolites and pathways associated with NAFLD by including both genetic and non-genetic factors in statistical analyses. We genotyped six genetic variants in the PNPLA3, TM6SF2, MBOAT7, GCKR, PPP1R3B, and HSD17B13 genes reported to be associated with NAFLD. Non-targeted metabolomic profiling was performed from plasma samples. We applied a previously validated fatty liver index to identify participants with NAFLD. First, we associated the six genetic variants with 1098 metabolites in 2 339 men without NAFLD to determine the effects of the genetic variants on metabolites, and then in 2 535 men with NAFLD to determine the joint effects of genetic variants and non-genetic factors on metabolites. We identified several novel metabolites and metabolic pathways, especially for PNPLA3, GCKR, and PPP1R38 variants relevant to the pathophysiology of NAFLD. Importantly, we showed that each genetic variant for NAFLD had a specific metabolite signature. The plasma metabolite signature was unique for each genetic variant, suggesting that several metabolites and different pathways are involved in the risk of NAFLD. The FLI index reliably identifies metabolites for NAFLD in large population-based studies.
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Metabolomic analysis shows dysregulation in amino acid and NAD+ metabolism in palmitate treated hepatocytes and plasma of non-alcoholic fatty liver disease spectrum. Biochem Biophys Res Commun 2023; 643:129-138. [PMID: 36603530 DOI: 10.1016/j.bbrc.2022.12.078] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 12/29/2022]
Abstract
There is an alarming increase in incidence of fatty liver disease worldwide. The fatty liver disease spectrum disease ranges from simple steatosis (NAFL) to steatohepatitis (NASH) which culminates in cirrhosis and cancer. Altered metabolism is a hallmark feature associated with fatty liver disease and palmitic acid is the most abundant saturated fatty acid, therefore, the aim of this study was to compare metabolic profiles altered in hepatocytes treated with palmitic acid and also the differentially expressed plasma metabolites in spectrum of nonalcoholic fatty liver. The metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS) platform. Hepatocyte cell lines PH5CH8 and HepG2 cells when treated with 400 μM dose of palmitic acid showed typical features of steatosis. Metabolomic analysis of lipid treated hepatocyte cell lines showed differential changes in phenylalanine and tyrosine pathways, fatty acid metabolism and bile acids. The key metabolites tryptophan, kynurenine and carnitine differed significantly between subjects with NAFL, NASH and those with cirrhosis. As the tryptophan-kynurenine axis is also involved in denovo synthesis of NAD+, we found significant alterations in the NAD+ related metabolites in both palmitic acid treated and also fatty liver disease with cirrhosis. The study underscores the importance of amino acid and NAD+supplementation as promising strategies in fatty liver disorder.
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50
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Rigamonti AE, Frigerio G, Caroli D, De Col A, Cella SG, Sartorio A, Fustinoni S. A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study. Nutrients 2023; 15:529. [PMID: 36771236 PMCID: PMC9921209 DOI: 10.3390/nu15030529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)-in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Gianfranco Frigerio
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue Du Swing, L-4367 Belvaux, Luxembourg
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandra De Col
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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