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El-Kurjieh A, Al-Arab R, Hachem QA, Ibrahim JN, Kobeissy PH. ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target. Lipids Health Dis 2025; 24:74. [PMID: 40001058 PMCID: PMC11853604 DOI: 10.1186/s12944-025-02491-z] [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: 11/22/2024] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Elevated incidence of metabolic disorders has been reported worldwide in the recent decade, highlighting the need for developing efficient therapies. These diseases result from a complex interplay of various factors that contribute to disease progression, complications, and resistance to current treatment options. Acetyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) is a nucleo-cytosolic enzyme with both lipogenic and metabolic regulatory roles. Studies on ACSS2 have shown that it is involved in pathways commonly dysregulated in metabolic disorders, leading to fat deposition and disrupted cellular signaling. Although multiple studies have suggested a role of ACSS2 in the metabolic rewiring during tumorigenesis, few studies have examined its involvement in the pathophysiology of metabolic diseases. Recent evidence indicates that ACSS2 may contribute to the pathogenesis of various metabolic disorders making its examination of great interest and potentially aiding in the development of new therapeutic strategies. The objective of this review is to summarize the current understanding of ACSS2's role in metabolic disorders and its potential as a therapeutic target.
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Affiliation(s)
- Alaa El-Kurjieh
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Reem Al-Arab
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Qamar Abou Hachem
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - José-Noel Ibrahim
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
| | - Philippe Hussein Kobeissy
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
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2
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Miura Y, Voican C, Sakai Y, Nishikawa M, Leclerc E. A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD. Toxicol Appl Pharmacol 2025; 495:117185. [PMID: 39631537 DOI: 10.1016/j.taap.2024.117185] [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: 09/10/2024] [Revised: 11/14/2024] [Accepted: 11/29/2024] [Indexed: 12/07/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as NAFLD) is a common liver disease worldwide and carries the risk of progressing to severe liver conditions, such as fibrosis and liver cancer. In the context of MASLD, evaluating fat accumulation in the liver and the subsequent production of oxidative stress is essential to understand the disease propagation. However, clinical studies using human patients to investigate the fat accumulation and the onset of oxidative stress in MASLD face ethical and technical challenges, highlighting the importance of alternative methods. To understand the relationship between fatty acid metabolism, lipid accumulation, oxidative stress generation, and antioxidant mechanisms in hepatocytes, we proposed a new mathematical model. The importance of this model lies in its ability to track the time-dependent changes in oxidative stress and glutathione concentration in response to the input of fatty acids. Furthermore, the model allows for the evaluation of the effects of altering the activity of the key enzymes involved in those mechanisms. Our model is anticipated to provide new insights into MASLD therapy strategies by identifying key pathways and predicting the effects of drug-induced changes in enzyme activity.
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Affiliation(s)
- Yuki Miura
- Department of Chemical System Engineering, Graduate school of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Cosmin Voican
- Department of Hepatogastroenterology and Nutrition, Antoine-Béclère University Hospital, AP-HP Paris-Saclay University, 92140 Clamart, France; INSERM U996, 91400 Orsay, France; Faculty of Medicine, Paris-Saclay University, 94270 Le Kremlin-Bicêtre, France
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, Graduate school of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.; CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
| | - Masaki Nishikawa
- Department of Chemical System Engineering, Graduate school of Engineering, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Eric Leclerc
- CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
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Zhang X, Zheng Y, Yang J, Yang Y, He Q, Xu M, Long F, Yang Y. Abnormal ac4C modification in metabolic dysfunction associated steatotic liver cells. Sci Rep 2025; 15:1013. [PMID: 39762452 PMCID: PMC11704021 DOI: 10.1038/s41598-024-84564-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear due to the complexity of its etiology. The emerging field of the epitranscriptome has shown significant promise in advancing the understanding of disease pathogenesis and developing new therapeutic approaches. Recent research has demonstrated that N4-acetylcytosine (ac4C), an RNA modification within the epitranscriptome, is implicated in progression of various diseases. However, the role of ac4C modification in MASLD remains unexplored. Herein, we performed acRIP-ac4c-seq and RNA-seq analysis in free fatty acids-induced MASLD model cells, identifying 2128 differentially acetylated ac4C sites, with 1031 hyperacetylated and 1097 hypoacetylated peaks in MASLD model cells. Functional enrichments analysis showed that ac4C differentially modified genes were significantly involved in processes related to MASLD, such as nuclear transport and MAP kinase (MAPK) signaling pathway. We also identified 341 differentially expressed genes (DEGs), including 61 lncRNAs and 280 mRNAs, between control and MASLD model cells. Bioinformatics analysis showed that DEGs were significantly enriched in long-chain fatty acid biosynthetic process. Notably, 118 genes exhibited significant changes in both ac4C modification and expression levels in MASLD model cells. Among these proteins, JUN, caveolin-1 (CAV1), fatty acid synthase (FASN), and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) were identified as core proteins through protein-protein interaction (PPI) network analysis using cytoscape software. Collectively, our findings establish a positive correlation between ac4C modification and the pathogenesis of MASLD and suggest that ac4C modification may serve as a therapeutic target for MASLD.
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Affiliation(s)
- Xiqian Zhang
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Yaxian Zheng
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Jing Yang
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Yan Yang
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Qin He
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Min Xu
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China
| | - Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Women's and Children's Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610041, China.
| | - Yujie Yang
- Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China.
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Muralidharan S, Lee JWJ, Lim YS, Muthiah M, Tan E, Demicioglu D, Shabbir A, Loo WM, Koo CS, Lee YM, Soon G, Wee A, Halisah N, Abbas S, Ji S, Triebl A, Burla B, Koh HWL, Chan YS, Lee MC, Ng HH, Wenk MR, Torta F, Dan YY. Serum lipidomic signatures in patients with varying histological severity of metabolic-dysfunction associated steatotic liver disease. Metabolism 2025; 162:156063. [PMID: 39522592 DOI: 10.1016/j.metabol.2024.156063] [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: 05/03/2024] [Revised: 10/13/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Patients with metabolic associated steatohepatitis (MASH) with fibrosis are at greatest risk of liver and cardiovascular complications. To identify such at-risk MASLD patients, physicians are still reliant on invasive liver biopsies. This study aimed to identify circulating lipidomic signatures to better identify patients with MASH in a multi-ethnic Asian cohort. APPROACH & RESULTS A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures for MASLD, at-risk MASH and advanced fibrosis were identified. 210 lipids showed significant differences for varying histological subtypes of MASLD. Majority of these lipids were associated with liver steatosis (198/210). We identified a panel of 13 lipids associated with lobular inflammation, ballooning and significant fibrosis. Of note, dihexosylceramides were novel markers for significant fibrosis. Using the serum lipidome alone, we could stratify patients with MASLD (AUROC 0.863), as well as those with at-risk MASH (AUROC 0.912) and advanced fibrosis (AUROC 0.95). The lipidomic at-risk MASH predictor, using 14 markers, was independently validated (n = 105) with AUROC 0.76. CONCLUSIONS The dynamic shift in serum lipid profile was associated with progressive histological stages of MASLD, providing surrogate markers for distinguishing stages of MASLD as well as identifying novel pathways in the pathogenesis.
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Affiliation(s)
- Sneha Muralidharan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore
| | - Jonathan W J Lee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology & Hepatology, National University Hospital, Singapore; iHealthtech, National University of Singapore, Singapore
| | - Yee Siang Lim
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology & Hepatology, National University Hospital, Singapore
| | - Eunice Tan
- Division of Gastroenterology & Hepatology, National University Hospital, Singapore
| | | | - Asim Shabbir
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Surgery, National University Hospital, Singapore
| | - Wai Mun Loo
- Division of Gastroenterology & Hepatology, National University Hospital, Singapore
| | - Chieh Sian Koo
- Division of Gastroenterology & Hepatology, National University Hospital, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology & Hepatology, National University Hospital, Singapore
| | - Gwyneth Soon
- Department of Pathology, National University Hospital, Singapore
| | - Aileen Wee
- Department of Pathology, National University Hospital, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nur Halisah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sakinah Abbas
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shanshan Ji
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore
| | - Alexander Triebl
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore
| | - Bo Burla
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore
| | - Hiromi W L Koh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Yun Shen Chan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Mei Chin Lee
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Huck Hui Ng
- Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Markus R Wenk
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore; Precision Medicine Translational Research Programme and Department of Biochemistry, National University of Singapore, Singapore
| | - Federico Torta
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore; Precision Medicine Translational Research Programme and Department of Biochemistry, National University of Singapore, Singapore; Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology & Hepatology, National University Hospital, Singapore.
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Samant V, Prabhu A. Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics. Life Sci 2024; 359:123225. [PMID: 39522716 DOI: 10.1016/j.lfs.2024.123225] [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: 06/08/2024] [Revised: 08/09/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Chronic diseases linked with sedentary lifestyles and poor dietary habits are increasingly common in modern society. Exercise is widely acknowledged to have a plethora of health benefits, including its role in primary prevention of various chronic conditions like type 2 diabetes mellitus, obesity, cardiovascular disease, and several musculoskeletal as well as degenerative disorders. Regular physical activity induces numerous physiological adaptations that contribute to these positive effects, primarily observed in skeletal muscle but also impacting other tissues. There is a growing interest among researchers in developing pharmaceutical interventions that mimic the beneficial effects of exercise for therapeutic applications. Exercise mimetic medications have the potential to be helpful aids in enhancing functional outcomes for patients with metabolic dysfunction, neuromuscular and musculoskeletal disorders. Some of the potential targets for exercise mimetics include pathways involved in metabolism, mitochondrial function, inflammation, and tissue regeneration. The present review aims to provide an exhaustive overview of the current understanding of exercise physiology, the role of exerkines and biomolecular pathways, and the potential applications of exercise mimetic drugs for the treatment of several diseases.
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Affiliation(s)
- Vedant Samant
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Arati Prabhu
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
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Liu Y, Fan Y, Liu J, Liu X, Li X, Hu J. Application and mechanism of Chinese herb medicine in the treatment of non-alcoholic fatty liver disease. Front Pharmacol 2024; 15:1499602. [PMID: 39605910 PMCID: PMC11598537 DOI: 10.3389/fphar.2024.1499602] [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: 09/21/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition closely associated with metabolic syndrome, with its incidence rate continuously rising globally. Recent studies have shown that the development of NAFLD is associated with insulin resistance, lipid metabolism disorder, oxidative stress and endoplasmic reticulum stress. Therapeutic strategies for NAFLD include lifestyle modifications, pharmacological treatments, and emerging biological therapies; however, there is currently no specific drug to treat NAFLD. However Chinese herb medicine (CHM) has shown potential in the treatment of NAFLD due to its unique therapeutic concepts and methods for centuries in China. This review aims to summarize the pathogenesis of NAFLD and some CHMs that have been shown to have therapeutic effects on NAFLD, thus enriching the scientific connotation of TCM theories and facilitating the exploration of TCM in the treatment of NAFLD.
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Affiliation(s)
- Yuqiao Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Fan
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jibin Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyang Liu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiuyan Li
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingqing Hu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Xin-Huangpu Joint Innovation Institute of Chinese Medicine, Guangzhou, China
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7
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Gamboa-Gómez CI, Morales-Castro J, Barragan-Zuñiga J, Herrera MD, Zamilpa-Álvarez A, Gónzalez JL, Martínez-Aguilar G, Morales-Castro EP, Anese M, Alongi M. Influence of coffee roasting degree on antioxidant and metabolic parameters: Comprehensive in vitro and in vivo analysis. Curr Res Food Sci 2024; 9:100861. [PMID: 39398976 PMCID: PMC11470189 DOI: 10.1016/j.crfs.2024.100861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 10/15/2024] Open
Abstract
This study aimed to assess the impact of roasting degree on antioxidant and metabolic parameters in vitro and in vivo. In vitro, we evaluated radical scavenging, lipid peroxidation, and the activity of digestive enzymes (α-glucosidase, α-amylase, and lipase). In vivo, we first examined coffee's effect on carbohydrate and lipid absorption in healthy rats, followed by a chronic evaluation of metabolic disorders and antioxidant markers using a diet-induced obesity model. In vitro results revealed that increased roasting degree reduced the antioxidant capacity of coffee brews. All brews showed lower inhibition of α-glucosidase and α-amylase, and lipase inhibition compared to the positive control (acarbose or orlistat). In vivo, all roasting degrees consistently reduced postprandial glucose levels by 20%. Notably, coffee with a high roasting degree (HRD) decreased serum triglycerides (TG) by ∼44% after a lipid load, while other roasts did not. Chronic administration of unroasted (UN) or HRD coffee significantly reduced weight gain compared to the obese control (∼15% and ∼10%, respectively). Notably, all coffee samples improved lipid metabolism parameters. UN and HRD coffee significantly decreased adipocyte volume by 58% and 48%, respectively, compared to the obese control. Additionally, all groups exhibited less than 30% hepatic lipid droplets independent of roasting degree. HRD treatment notably increased liver catalase (CAT) activity and reduced lipid peroxidation in serum (∼90%), liver (∼59%), and adipose tissue (∼37%) compared to the obese control group. These findings suggest that HRD in coffee may confer certain biological advantages.
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Affiliation(s)
- Claudia I. Gamboa-Gómez
- Unidad de Investigación Biomédica del Instituto Mexicano del Seguro Social, Canoas 100, 34067, Durango, Mexico
| | - Juliana Morales-Castro
- TecNM/Instituto Tecnológico de Durango, División de Estudios de Posgrado de Investigación, Blvd. Felipe Pescador 1830 Ote, Colonia Nueva Vizcaya, C.P. 34080, Durango, Dgo, Mexico
| | - Jazel Barragan-Zuñiga
- Centro Estatal de Cancerología, Secretaria de Salud Durango, Av. 5 de Febrero esq, Antonio Norman Fuentes S/N, Zona Centro, c.p. 34000, Durango, Dgo, Mexico
| | - Mayra Denise Herrera
- Instituto Nacional de Investigaciones Forestales Agrícolas y Pecuarias, Campo Experimental Zacatecas, Kilómetro 24.5, 98500, Zacatecas, Fresnillo, Zac, Mexico
| | | | - José Luis Gónzalez
- Departamento de Patología, Hospital General de Zona No.1, Instituto Mexicano del Seguro Social, Canoas S/N, 34067, Durango, Mexico
| | - Gerardo Martínez-Aguilar
- Facultad de Medicina y Nutrición. Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa s/n, C.P, 34000, Durango, Mexico
| | - Elisa P. Morales-Castro
- TecNM/Instituto Tecnológico de Durango, División de Estudios de Posgrado de Investigación, Blvd. Felipe Pescador 1830 Ote, Colonia Nueva Vizcaya, C.P. 34080, Durango, Dgo, Mexico
| | - Monica Anese
- Department of Agricultural, Food, Environmental and Animal Sciences, University of Udine, Via Sondrio 2/A, 33100, Udine, Italy
| | - Marilisa Alongi
- Department of Agricultural, Food, Environmental and Animal Sciences, University of Udine, Via Sondrio 2/A, 33100, Udine, Italy
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8
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Fang Z, Liu C, Yu X, Yang K, Yu T, Ji Y, Liu C. Identification of neutrophil extracellular trap-related biomarkers in non-alcoholic fatty liver disease through machine learning and single-cell analysis. Sci Rep 2024; 14:21085. [PMID: 39256536 PMCID: PMC11387488 DOI: 10.1038/s41598-024-72151-2] [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: 05/24/2024] [Accepted: 09/04/2024] [Indexed: 09/12/2024] Open
Abstract
Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.
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Affiliation(s)
- Zhihao Fang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Changxu Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xiaoxiao Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Kai Yang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Tianqi Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yanchao Ji
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chang Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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9
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Son WH, Park HT, Jeon BH, Ha MS. Effects of fermented oyster extract supplementation on free fatty acid and liver enzymes in older women with obesity. Phys Act Nutr 2024; 28:58-63. [PMID: 39501695 PMCID: PMC11540988 DOI: 10.20463/pan.2024.0024] [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: 07/02/2024] [Revised: 09/02/2024] [Accepted: 09/30/2024] [Indexed: 11/09/2024] Open
Abstract
PURPOSE This study aimed to investigate the effects of a 12-week intake of fermented oyster extract on free fatty acids and liver enzymes in older women with obesity and to provide basic data for improving liver function in older individuals with obesity. METHODS A randomized, double-blind, placebo-controlled clinical trial aimed to confirm the effects of fermented oyster extract intake on free fatty acid (FFA) levels and liver function in older women with obesity. The study included 40 older women with obesity with a body mass index ≥ 25 kg/m2. Participants were divided into a fermented oyster intake group (n = 20) and control group (n = 20). Serum FFA, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) levels were measured at weeks 0 and 12. RESULTS Our results showed an interaction effect between the two groups in terms of serum FFA levels (p<0.05), with a post-intervention decrease in the FSO group (p<0.05). AST, ALT, and GGT levels also showed an interaction effect between the two groups (p<0.05), with a significant postintervention decrease in the FSO group (p<0.05). CONCLUSION The intake of fermented oyster extract significantly reduced FFA, ALT, AST, and GGT levels. These results suggested that the consumption of fermented oyster extract may improve liver function. However, the findings of this study were limited to elderly women with obesity, and the relatively short intake period and small sample size may limit the generalization of the results.
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Affiliation(s)
- Woo Hyeon Son
- Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea
| | - Hyun Tae Park
- Graduate School of Health Care and Sciences, College of Health Science, Dong-A University, Busan, Republic of Korea
| | - Byeong Hwan Jeon
- Department of Sports and Health Science, College of Arts, Kyungsung University, Busan, Republic of Korea
| | - Min-Seong Ha
- Laboratory of Sports Conditioning: Nutrition Biochemistry and Neuroscience, Department of Sport Science, College of Arts and Sports, University of Seoul, Seoul, Republic of Korea
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10
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Bjørndal B, Tungland SL, Bohov P, Sydnes MO, Dankel SN, Madsen L, Berge RK. Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids. LIVER RESEARCH 2024; 8:152-164. [PMID: 39957749 PMCID: PMC11771272 DOI: 10.1016/j.livres.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/24/2024] [Accepted: 09/03/2024] [Indexed: 02/18/2025]
Abstract
Background and objective Metabolic associated fatty liver disease (MAFLD) is associated with abnormal lipid metabolism. Mitochondrial dysfunction is considered an important factor in the onset of MAFLD, whereas altered fatty acid composition has been linked to the severity of the disease. Tetradecylthioacetic acid (TTA), shown to induce mitochondrial proliferation and alter the fatty acid composition, was used to delay the accumulation of hepatic triacylglycerol. This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet. Methods C57BL/6 mice (n = 40) were fed high-carbohydrate diets supplemented with meldonium, TTA, or a combination of meldonium and TTA for 21 days. Lipid levels were determined in liver samples, and fatty acid composition was measured in both liver and plasma samples. Additionally, desaturase and elongase activities were estimated. The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples, whereas carnitines, their precursors, and acylcarnitines were measured in plasma samples. Results The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines. Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA. The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase (D6D; C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6), and increased circulating levels of C18:4n-3 and C18:3n-6 (gamma-linolenic acid). TTA mitigated meldonium-induced triacylglycerol levels by 80% and attenuated the estimated D6D activities, and elongation of n-6 polyunsaturated fatty acids (PUFAs). TTA also attenuated the meldonium-mediated reduction of C24:1n-9 (nervonic acid), possibly by stimulating Elovl 5 and increased elongation of erucic acid (C22:1n-9) to nervonic acid. The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels, while the estimated activities of D6D correlated positively. Conclusion Circulating levels of gamma-linolenic acid, along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities, were associated with hepatic triacylglycerol levels.
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Affiliation(s)
- Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Sports, Physical Activity and Food, Western Norway University of Applied Sciences, Bergen, Norway
| | - Siri Lunde Tungland
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Pavol Bohov
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Magne O. Sydnes
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Simon N. Dankel
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lise Madsen
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Rolf K Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
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11
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Pogoda W, Koczur J, Stachowicz A, Madej J, Olszanecki R, Suski M. Multi-layered metabolic effects of trehalose on the liver proteome in apoE-knockout mice model of liver steatosis. Pharmacol Rep 2024; 76:902-909. [PMID: 38913153 PMCID: PMC11294376 DOI: 10.1007/s43440-024-00615-3] [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: 03/18/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 06/25/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease has been well documented as a key independent risk factor for the development of atherosclerosis. A growing body of evidence suggests that due to its numerous favorable molecular effects, trehalose may exert beneficial effects in counteracting liver steatosis. In our previous study, we described the antiatherosclerotic and antisteatotic properties of trehalose, which we attributed to the induction of autophagy. Considering the pleiotropic activities of trehalose, our present study aimed to extend our preliminary results with the comprehensive examination of proteome-wide changes in the livers of high-fat-fed apoE-/- mice. METHODS Thus, we applied modern, next-generation proteomic methodology to comprehensively analyze the effects of trehalose on the alterations of liver proteins in apoE-/- mice. RESULTS Our proteomic analysis showed that the administration of trehalose elicited profound changes in the liver proteome of apoE-/- mice. The collected data allowed the identification and quantitation of 3 681 protein groups of which 129 were significantly regulated in the livers of trehalose-treated apoE-/- mice. CONCLUSIONS The presented results are the first to highlight the effects of disaccharide on the induction of proteins mainly related to the metabolism and elimination of lipids, especially by peroxisomal β-oxidation. Our study provides evidence for the pleiotropic activity of trehalose, extending our initial observations of its potential mechanisms responsible for mitigating of liver steatosis, which paves the way for new pharmacological strategies in fatty liver disease.
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Affiliation(s)
- Weronika Pogoda
- Proteomics Laboratory, Centre for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Jakub Koczur
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Aneta Stachowicz
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Józef Madej
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Rafał Olszanecki
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Maciej Suski
- Proteomics Laboratory, Centre for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Krakow, Poland.
- Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
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12
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Oshida N, Oh S, Kim B, Miura I, Hasegawa N, Komine S, Isobe T, Shoda J. Muscle Quality as a Potential Diagnostic Marker of Advanced Liver Fibrosis in Patients with Non-alcoholic Fatty Liver Disease. J Obes Metab Syndr 2024; 33:143-154. [PMID: 38735655 PMCID: PMC11224921 DOI: 10.7570/jomes23072] [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: 10/29/2023] [Revised: 12/22/2023] [Accepted: 02/23/2024] [Indexed: 05/14/2024] Open
Abstract
Background Muscle-liver crosstalk plays an important role in the development and progression of non-alcoholic fatty liver disease (NAFLD). The measurement of muscle echo-intensity during ultrasonography is a real-time, non-invasive method of assessing muscle quality. In this retrospective study, we investigated the significance of poor muscle quality (namely, a greater mass of non-contractile tissue, including intramuscular fat) as a risk factor for advanced liver fibrosis and considered whether it may represent a useful tool for the diagnosis of advanced liver fibrosis. Methods We analyzed data from 307 patients with NAFLD (143 men and 164 women) who visited the University of Tsukuba Hospital between 2017 and 2022. The patients were stratified into the following tertiles of muscle quality according to their muscle echo-intensity on ultrasonography: modest (84.1 arbitrary units [A.U.]), intermediate (97.4 A.U.), and poor (113.6 A.U.). We then investigated the relationships between muscle quality and risk factors for advanced liver fibrosis and calculated appropriate cutoff values. Results Patients with poor muscle quality showed a significant, 7.6-fold greater risk of liver fibrosis compared to those with modest muscle quality. Receiver operating characteristic curve analysis showed that muscle quality assessment was as accurate as the fibrosis-4 index and NAFLD fibrosis score in screening for liver fibrosis and superior to the assessment of muscle quantity and strength, respectively. Importantly, a muscle echo-intensity of ≥92.4 A.U. may represent a useful marker of advanced liver fibrosis. Conclusion Muscle quality may represent a useful means of identifying advanced liver fibrosis, and its assessment may become a useful screening tool in daily practice.
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Affiliation(s)
- Natsumi Oshida
- Division of Laboratory Medicine, Tsukuba University Hospital, Tsukuba, Japan
| | - Sechang Oh
- Faculty of Rehabilitation, R Professional University of Rehabilitation, Tsuchiura, Japan
| | - Bokun Kim
- Future Convergence Research Institute, Changwon National University, Changwon, Korea
| | - Ikuru Miura
- Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
| | - Naoyuki Hasegawa
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Shoichi Komine
- Faculty of Human Care, Teikyo Heisei University, Tokyo, Japan
| | - Tomonori Isobe
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Junichi Shoda
- Department of Medical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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Jeong Y, Lee BJ, Hur W, Lee M, Han SH. Associations of Insulin Resistance and High-Sensitivity C-Reactive Protein with Metabolic Abnormalities in Korean Patients with Type 2 Diabetes Mellitus: A Preliminary Study. Metabolites 2024; 14:371. [PMID: 39057694 PMCID: PMC11279201 DOI: 10.3390/metabo14070371] [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: 04/10/2024] [Revised: 06/27/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
We conducted this single-center, retrospective, cohort study to examine whether insulin resistance (IR) and high-sensitivity C-reactive protein (hsCRP) have a relationship with metabolic abnormalities in patients with type 2 diabetes mellitus (T2DM). In a total of 3758 patients (n = 3758) with T2DM, we analyzed medical records and thereby evaluated their baseline characteristics such as age, sex, duration of T2DM, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, body mass index (BMI), visceral fat thickness (VFT), fasting plasma insulin levels, C-peptide levels, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), homeostatic model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of β-cell function (HOMA-β), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), albuminuria, intima-media thickness (IMT) and hsCRP. The patients were stratified according to the tertile of the K index of the insulin tolerance test (KITT) or hsCRP. Thus, they were divided into the lowest (≥2.37), middle (1.54-2.36) and highest tertile (0-1.53) of KITT and the lowest (0.00-0.49), middle (0.50-1.21) and highest tertile (≥1.22) of hsCRP. Moreover, associations of KITT and hsCRP with metabolic abnormalities, such as steatotic liver disease (SLD), metabolic syndrome (MetS), albuminuria, diabetic retinopathy and carotid atherosclerosis, were also analyzed. There was a significant positive correlation between the prevalence of SLD, MetS, albuminuria and diabetic retinopathy and KITT (p < 0.001). Moreover, there was a significant positive association between the prevalence of SLD, MetS and albuminuria and hsCRP (p < 0.001). In conclusion, our results indicate that clinicians should consider the relationships of IR and hsCRP with metabolic abnormalities in the management of patients with T2DM. However, further large-scale, prospective, multi-center studies are warranted to confirm our results.
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Affiliation(s)
- Yuchul Jeong
- Department of Internal Medicine, Chungna Good Hospital, Incheon 22738, Republic of Korea
| | - Beom Jun Lee
- St. Mary’s Best ENT Clinic, Seoul 08849, Republic of Korea
| | - Wonjai Hur
- Department of Internal Medicine, Sejong General Hospital, Bucheon 14754, Republic of Korea
| | - Minjoon Lee
- Department of Internal Medicine, BS General Hospital, Incheon 23037, Republic of Korea
| | - Se-Hyeon Han
- Department of Companion Animal Industry, College of Health Science, Honam University, Gwangju 62399, Republic of Korea
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14
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Li S, Xiong F, Zhang S, Liu J, Gao G, Xie J, Wang Y. Oligonucleotide therapies for nonalcoholic steatohepatitis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102184. [PMID: 38665220 PMCID: PMC11044058 DOI: 10.1016/j.omtn.2024.102184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.
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Affiliation(s)
- Sixu Li
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
| | - Feng Xiong
- Department of Cardiology, The Third People’s Hospital of Chengdu, Chengdu 610031, China
| | - Songbo Zhang
- Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jinghua Liu
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Jun Xie
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Yi Wang
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
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Ogłuszka M, Chen CY, Poławska E, Starzyński RR, Liput K, Siekierko U, Pareek CS, Pierzchała M, Kang JX. Elevated tissue status of omega-3 fatty acids protects against age-related telomere attrition in fat-1 transgenic mice. Clin Nutr 2024; 43:1488-1494. [PMID: 38718720 DOI: 10.1016/j.clnu.2024.05.001] [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: 02/10/2024] [Revised: 04/20/2024] [Accepted: 05/01/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND & AIMS Leukocyte telomere length (LTL) is a biomarker of aging that may be influenced by dietary factors. Omega-3 fatty acids (n-3 FA) have been suggested to affect LTL. However, research on this effect has been inconclusive. The aim of the study was to test the hypothesis about the positive effect of n-3 FA on LTL. METHODS Fat-1 transgenic mice, which can convert omega-6 fatty acids (n-6 FA) to n-3 FA and have elevated levels of endogenous n-3 FA in their tissues, were used to study the effects of n-3 FA on LTL at different ages. Blood samples from 10-month-old wild-type (WT) mice (n = 10) and fat-1 mice (n = 10) and 3-month-old WT mice (n = 5) and fat-1 mice (n = 5) were used to measure relative and absolute LTL. The levels of proteins critical for telomere maintenance were examined by Western blot analysis. RESULTS Fat-1 transgenic mice had longer leukocyte telomeres than their WT siblings, suggesting a slower rate of age-related telomere shortening in fat-1 mice. In animals aged 10 months, the LTL was significantly longer in fat-1 than in WT mice (mean ± SEM; relative LTL: WT = 1.00 ± 0.09 vs. fat-1: 1.25 ± 0.05, P = 0.031; absolute LTL: WT = 64.41 ± 6.50 vs. fat-1: 78.53 ± 3.86, P = 0.048). The difference in LTL observed in three-month-old mice was insignificant, however the mean LTL was still longer in fat-1 mice than in the WT mice. Fat-1 mice also had abundant levels of two shelterin proteins: TRF1 (27%, P = 0.028) and TRF2 (47%, P = 0.040) (telomeric repeat binding factor 1 and 2) compared to WT animals. CONCLUSION This study, for the first time in a unique animal model free of dietary confounders, has demonstrated that increased levels of n-3 FA in tissues can reduce telomere attrition. The data presented indicate the possibility of using omega-3 fatty acids to reduce accelerated telomere attrition and, consequently, counteract premature aging and reduce the risk of age-related diseases.
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Affiliation(s)
- Magdalena Ogłuszka
- Department of Genomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzębiec, Poland.
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ewa Poławska
- Department of Genomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzębiec, Poland
| | - Rafał R Starzyński
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzębiec, Poland
| | - Kamila Liput
- Department of Genomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzębiec, Poland
| | - Urszula Siekierko
- Department of Meat and Fat Technology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology-State Research Institute, Poznań, Poland
| | - Chandra S Pareek
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Toruń, Poland
| | - Mariusz Pierzchała
- Department of Genomics, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzębiec, Poland
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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16
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Fang Z, Shen G, Wang Y, Hong F, Tang X, Zeng Y, Zhang T, Liu H, Li Y, Wang J, Zhang J, Gao A, Qi W, Yang X, Zhou T, Gao G. Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease. Signal Transduct Target Ther 2024; 9:66. [PMID: 38472195 PMCID: PMC10933339 DOI: 10.1038/s41392-024-01781-9] [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: 09/16/2023] [Revised: 02/14/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.
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Affiliation(s)
- Zhenzhen Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Gang Shen
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yina Wang
- Department of VIP Medical Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Fuyan Hong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiumei Tang
- Physical Examination Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yongcheng Zeng
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ting Zhang
- Department of Clinical Laboratory, Guangzhou First People's Hospital, Guangzhou, 510080, China
| | - Huanyi Liu
- Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yanmei Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jinhong Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jing Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Anton Gao
- Department of Health Sciences, College of Health Solutions, Arizona State University, Tempe, USA
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xia Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Ti Zhou
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Diabetology, Guangzhou, 510080, China.
| | - Guoquan Gao
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Viswanath A, Fouda S, Fernandez CJ, Pappachan JM. Metabolic-associated fatty liver disease and sarcopenia: A double whammy. World J Hepatol 2024; 16:152-163. [PMID: 38495287 PMCID: PMC10941748 DOI: 10.4254/wjh.v16.i2.152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/26/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
The prevalence of metabolic-associated fatty liver disease (MAFLD) has increased substantially in recent years because of the global obesity pandemic. MAFLD, now recognized as the number one cause of chronic liver disease in the world, not only increases liver-related morbidity and mortality among sufferers but also worsens the complications associated with other comorbid conditions such as cardiovascular disease, type 2 diabetes mellitus, obstructive sleep apnoea, lipid disorders and sarcopenia. Understanding the interplay between MAFLD and these comorbidities is important to design optimal therapeutic strategies. Sarcopenia can be either part of the disease process that results in MAFLD (e.g., obesity or adiposity) or a consequence of MAFLD, especially in the advanced stages such as fibrosis and cirrhosis. Sarcopenia can also worsen MAFLD by reducing exercise capacity and by the production of various muscle-related chemical factors. Therefore, it is crucial to thoroughly understand how we deal with these diseases, especially when they coexist. We explore the pathobiological interlinks between MAFLD and sarcopenia in this comprehensive clinical update review article and propose evidence-based therapeutic strategies to enhance patient care.
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Affiliation(s)
- Aditya Viswanath
- School of Medicine, Leicester University, Leicester LE1 7RH, United Kingdom
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, Rmit University, Melbourne VIC, Australia
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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18
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Zhao Y, Fu W, Wang L. Biomarkers in aortic dissection: Diagnostic and prognostic value from clinical research. Chin Med J (Engl) 2024; 137:257-269. [PMID: 37620283 PMCID: PMC10836883 DOI: 10.1097/cm9.0000000000002719] [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: 02/11/2023] [Indexed: 08/26/2023] Open
Abstract
ABSTRACT Aortic dissection is a life-threatening condition for which diagnosis mainly relies on imaging examinations, while reliable biomarkers to detect or monitor are still under investigation. Recent advances in technologies provide an unprecedented opportunity to yield the identification of clinically valuable biomarkers, including proteins, ribonucleic acids (RNAs), and deoxyribonucleic acids (DNAs), for early detection of pathological changes in susceptible patients, rapid diagnosis at the bedside after onset, and a superior therapeutic regimen primarily within the concept of personalized and tailored endovascular therapy for aortic dissection.
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Affiliation(s)
- Yufei Zhao
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Vascular Surgery Institute,Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Weiguo Fu
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Vascular Surgery Institute,Zhongshan Hospital, Fudan University, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian 361015, China
| | - Lixin Wang
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Vascular Surgery Institute,Zhongshan Hospital, Fudan University, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian 361015, China
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Yoon Y, Kim YM, Lee S, Shin BC, Kim HL, Chung JH, Son M. Association between Neck Circumference and Chronic Kidney Disease in Korean Adults in the 2019-2021 Korea National Health and Nutrition Examination Survey. Nutrients 2023; 15:5039. [PMID: 38140298 PMCID: PMC10745966 DOI: 10.3390/nu15245039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/01/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Chronic kidney disease (CKD) is a major public health problem and a leading cause of cardiovascular disease and death. Early recognition and management of CKD risk factors are necessary to prevent its onset and progression. Neck circumference (NC) is a non-invasive and easily accessible anthropometric measure associated with central obesity and subcutaneous fat accumulation in the upper body. Our study aimed to explore the relationship between NC and the prevalence of CKD using data from the nationally representative Korea National Health and Nutrition Examination Survey (2019-2021). We analyzed data from 10,219 subjects (age > 19 years, no missing values). CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Logistic regression analysis was performed, which revealed a significant association between NC and CKD prevalence even after adjusting for confounding factors, both when NC was considered a continuous variable (OR [95% CI], 1.11 [1.03-1.19]) and in quartiles (Q1 as reference; Q2 OR [95% CI], 1.23 [0.91-1.67]; Q3 OR [95% CI], 1.59 [1.16-2.18]; Q4 OR [95% CI], 1.70 [1.16-2.50]). Our findings suggest that NC could be a simple and effective anthropometric measurement for identifying individuals at risk for CKD.
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Affiliation(s)
- Youngmin Yoon
- Division of Nephrology, Department of Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju 61453, Republic of Korea; (Y.Y.); (S.L.); (B.-C.S.); (H.-L.K.); (J.-H.C.)
| | - Yoo-min Kim
- Department of Obstetrics and Gynecology, Chung-Ang University Gwang-myung Hospital, Chung-Ang University College of Medicine, Gwangmyeong-si 14353, Republic of Korea;
| | - Somin Lee
- Division of Nephrology, Department of Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju 61453, Republic of Korea; (Y.Y.); (S.L.); (B.-C.S.); (H.-L.K.); (J.-H.C.)
| | - Byung-Chul Shin
- Division of Nephrology, Department of Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju 61453, Republic of Korea; (Y.Y.); (S.L.); (B.-C.S.); (H.-L.K.); (J.-H.C.)
| | - Hyun-Lee Kim
- Division of Nephrology, Department of Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju 61453, Republic of Korea; (Y.Y.); (S.L.); (B.-C.S.); (H.-L.K.); (J.-H.C.)
| | - Jong-Hoon Chung
- Division of Nephrology, Department of Medicine, Chosun University Hospital, Chosun University School of Medicine, Gwangju 61453, Republic of Korea; (Y.Y.); (S.L.); (B.-C.S.); (H.-L.K.); (J.-H.C.)
| | - Minkook Son
- Department of Physiology, Dong-A University College of Medicine, Busan 49201, Republic of Korea
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20
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Bahijri S, Eldakhakhny B, Enani S, Ajabnoor G, Al-Mowallad AS, Alsheikh L, Alhozali A, Alamoudi AA, Borai A, Tuomilehto J. Fibroblast Growth Factor 21: A More Effective Biomarker Than Free Fatty Acids and Other Insulin Sensitivity Measures for Predicting Non-alcoholic Fatty Liver Disease in Saudi Arabian Type 2 Diabetes Patients. Cureus 2023; 15:e50524. [PMID: 38222178 PMCID: PMC10787595 DOI: 10.7759/cureus.50524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2023] [Indexed: 01/16/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is more prevalent among individuals with type 2 diabetes (T2DM), elevating their risk of cardiovascular diseases (CVDs) and premature mortality. There is a need to modify treatment strategies to prevent or delay these adverse outcomes. Currently, there are no sensitive or specific biomarkers for predicting NAFLD in Saudi T2DM patients. Therefore, we aimed to explore the possibility of using fibroblast growth factor 21 (FGF-21), free fatty acids (FFAs), homeostatic model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as possible markers. Methodology In this study, a total of 67 T2DM patients were recruited. NAFLD was detected by ultrasonography in 28 patients. Plasma glucose, FFAs, FGF-21, and serum insulin were measured in fasting blood samples. HOMA-IR and QUICKI were calculated. The means of the two groups with and without NAFLD were statistically compared. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to assess the ability to identify NAFLD. Results The mean levels of FGF-21 and HOMA-IR were significantly higher and that of QUICKI was significantly lower in patients with NAFLD than in those without (p < 0.001, p = 0.023, and p = 0.018, respectively). FGF-21 had the highest AUC to identify NAFLD (AUC = 0.981, 95% confidence interval = 0.954-1, P < 0.001). The AUCs for HOMA-IR, QUICKI, and FFA were <0.7. The highest sensitivity, specificity, positive likelihood ratio, and the lowest negative likelihood ratio were found when FGF-21 was used to predict NAFLD. Conclusions FGF-21 may be used as a biomarker to predict NAFLD in people with T2DM due to its high sensitivity and specificity compared to the other markers.
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Affiliation(s)
- Suhad Bahijri
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Basmah Eldakhakhny
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Sumia Enani
- Department of Food and Nutrition, Faculty of Human Sciences and Design, King Abdulaziz University, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Ghada Ajabnoor
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Alaa S Al-Mowallad
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Lubna Alsheikh
- Department of Biochemistry, King Abdulaziz University, Jeddah, SAU
| | - Amani Alhozali
- Department of Internal Medicine, King Abdulaziz University Hospital, Jeddah, SAU
| | - Aliaa A Alamoudi
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
| | - Anwar Borai
- King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
| | - Jaakko Tuomilehto
- Department of Public Health, University of Helsinki, Helsinki, FIN
- Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, FIN
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Jayachandran M, Qu S. Non-alcoholic fatty liver disease and gut microbial dysbiosis- underlying mechanisms and gut microbiota mediated treatment strategies. Rev Endocr Metab Disord 2023; 24:1189-1204. [PMID: 37840104 DOI: 10.1007/s11154-023-09843-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/17/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is by far the most prevalent form of liver disease worldwide. It's also the leading cause of liver-related hospitalizations and deaths. Furthermore, there is a link between obesity and NAFLD risk. A projected 25% of the world's population grieves from NAFLD, making it the most common chronic liver disorder. Several factors, such as obesity, oxidative stress, and insulin resistance, typically accompany NAFLD. Weight loss, lipid-lowering agents, thiazolidinediones, and metformin help prominently control NAFLD. Interestingly, pre-clinical studies demonstrate gut microbiota's potential causal role in NAFLD. Increased intestinal permeability and unhindered transport of microbial metabolites into the liver are the major disruptions due to gut microbiome dysbiosis, contributing to the development of NAFLD by dysregulating the gut-liver axis. Hence, altering the pathogenic bacterial population using probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) could benefit patients with NAFLD. Therefore, it is crucial to acknowledge the importance of microbiota-mediated therapeutic approaches for NAFLD and comprehend the underlying mechanisms that establish a connection between NAFLD and gut microbiota. This review provides a comprehensive overview of the affiliation between dysbiosis of gut microbiota and the progress of NAFLD, as well as the potential benefits of prebiotic, probiotic, synbiotic supplementation, and FMT in obese individuals with NAFLD.
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Affiliation(s)
- Muthukumaran Jayachandran
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
- Shanghai center of Thyroid diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
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22
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Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development. Mol Cell Pediatr 2023; 10:16. [PMID: 37957462 PMCID: PMC10643747 DOI: 10.1186/s40348-023-00170-6] [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: 07/09/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. MAIN TEXT Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies.
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Affiliation(s)
- Lisa Ruck
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany.
| | - Susanna Wiegand
- Abteilung Interdisziplinär, Sozial-Pädiatrisches Zentrum, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Kühnen
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany
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23
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Fa P, Ke BG, Dupre A, Tsung A, Zhang H. The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease. Front Immunol 2023; 14:1292679. [PMID: 38022519 PMCID: PMC10652891 DOI: 10.3389/fimmu.2023.1292679] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an expanding worldwide health concern, and the underlying mechanisms contributing to its progression still need further exploration. Neutrophil extracellular traps (NETs) are intricate formations comprised of nuclear constituents and diverse antimicrobial granules that are released into the extracellular milieu by activated neutrophils upon various triggers, which play a pivotal part in the onset and advancement of NAFLD. NETs actively participate in the genesis of NAFLD by fostering oxidative stress and inflammation, ultimately resulting in hepatic fat accumulation and the escalation of liver injury. Recent insights into the interaction with other hepatic immune populations and mediators, such as macrophages and T regulatory cells, have revealed several important mechanisms that can trigger further liver injury. In conclusion, the formation of NETs emerged as an important factor in the development of NAFLD, offering a promising target for innovative therapeutic approaches against this debilitating condition. This comprehensive review seeks to compile existing studies exploring the involvement of NETs in the genesis of NAFLD and their influence on the immune response throughout the progression of NAFLD.
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Affiliation(s)
- Pengyan Fa
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Benjamin G. Ke
- School of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Abigail Dupre
- School of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Allan Tsung
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Hongji Zhang
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, United States
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24
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Ajuwon BI, Roper K, Richardson A, Lidbury BA. Routine blood test markers for predicting liver disease post HBV infection: precision pathology and pattern recognition. Diagnosis (Berl) 2023; 10:337-347. [PMID: 37725092 DOI: 10.1515/dx-2023-0078] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/25/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Early stages of hepatitis B virus (HBV) infection usually involve inflammation of the liver. Patients with chronic infection have an increased risk of progressive liver fibrosis, cirrhosis, and life-threatening clinical complications of end-stage hepatocellular carcinoma (HCC). CONTENT Early diagnosis of hepatic fibrosis and timely clinical management are critical to controlling disease progression and decreasing the burden of end-stage liver cancer. Fibrosis staging, through its current gold standard, liver biopsy, improves patient outcomes, but the clinical procedure is invasive with unpleasant post-procedural complications. Routine blood test markers offer promising diagnostic potential for early detection of liver disease without biopsy. There is a plethora of candidate routine blood test markers that have gone through phases of biomarker validation and have shown great promise, but their current limitations include a predictive ability that is limited to only a few stages of fibrosis. However, the advent of machine learning, notably pattern recognition, presents an opportunity to refine blood-based non-invasive models of hepatic fibrosis in the future. SUMMARY In this review, we highlight the current landscape of routine blood-based non-invasive models of hepatic fibrosis, and appraise the potential application of machine learning (pattern recognition) algorithms to refining these models and optimising clinical predictions of HBV-associated liver disease. OUTLOOK Machine learning via pattern recognition algorithms takes data analytics to a new realm, and offers the opportunity for enhanced multi-marker fibrosis stage prediction using pathology profile that leverages information across patient routine blood tests.
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Affiliation(s)
- Busayo I Ajuwon
- National Centre for Epidemiology and Population Health, ANU College of Health and Medicine, The Australian National University, Acton, Australian Capital Territory, Australia
- Department of Microbiology, Faculty of Pure and Applied Sciences, Kwara State University, Malete, Nigeria
| | - Katrina Roper
- National Centre for Epidemiology and Population Health, ANU College of Health and Medicine, The Australian National University, Acton, Australian Capital Territory, Australia
| | - Alice Richardson
- Statistical Support Network, The Australian National University, Acton, Australian Capital Territory, Australia
| | - Brett A Lidbury
- National Centre for Epidemiology and Population Health, ANU College of Health and Medicine, The Australian National University, Acton, Australian Capital Territory, Australia
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25
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Hendriks D, Brouwers JF, Hamer K, Geurts MH, Luciana L, Massalini S, López-Iglesias C, Peters PJ, Rodríguez-Colman MJ, Chuva de Sousa Lopes S, Artegiani B, Clevers H. Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis. Nat Biotechnol 2023; 41:1567-1581. [PMID: 36823355 PMCID: PMC10635827 DOI: 10.1038/s41587-023-01680-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 01/19/2023] [Indexed: 02/25/2023]
Abstract
The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB-/- and MTTP-/- organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.
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Affiliation(s)
- Delilah Hendriks
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
- Oncode Institute, Utrecht, The Netherlands.
| | - Jos F Brouwers
- Research Group Analysis Techniques in the Life Sciences, School of Life Sciences and Technology, Avans University of Applied Sciences, Breda, The Netherlands
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Karien Hamer
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Maarten H Geurts
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Léa Luciana
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Simone Massalini
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Carmen López-Iglesias
- The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Peter J Peters
- The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Maria J Rodríguez-Colman
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Benedetta Artegiani
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
| | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
- Oncode Institute, Utrecht, The Netherlands.
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
- University Medical Center Utrecht, Utrecht, The Netherlands.
- Pharma, Research and Early Development of F. Hoffmann-La Roche Ltd, Basel, Switzerland.
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Scheidl T, Wager J, Baker L, Brightwell A, Melan K, Larion S, Sarr O, Regnault T, Urbanski S, Thompson J. High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring. Biosci Rep 2023; 43:BSR20231060. [PMID: 37706282 PMCID: PMC10550783 DOI: 10.1042/bsr20231060] [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: 06/05/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.
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Affiliation(s)
- Taylor B. Scheidl
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Jessica L. Wager
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
| | - Larissa G. Baker
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Katrina M. Melan
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Sebastian Larion
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, U.S.A
| | - Ousseynou Sarr
- Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, Western University, London, ON, Canada
| | - Timothy RH. Regnault
- Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, Western University, London, ON, Canada
| | - Stefan J. Urbanski
- Department of Pathology, University of Calgary, Calgary, Alberta, Canada
| | - Jennifer A. Thompson
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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27
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Elbadawy M, Tanabe K, Yamamoto H, Ishihara Y, Mochizuki M, Abugomaa A, Yamawaki H, Kaneda M, Usui T, Sasaki K. Evaluation of the efficacy of mitochondrial fission inhibitor (Mdivi-1) using non-alcoholic steatohepatitis (NASH) liver organoids. Front Pharmacol 2023; 14:1243258. [PMID: 37900170 PMCID: PMC10600465 DOI: 10.3389/fphar.2023.1243258] [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: 06/20/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is known to progress to cirrhosis and hepatocellular carcinoma in some patients. Although NASH is associated with abnormal mitochondrial function related to lipid metabolism, mechanisms for the development and effective treatments are still unclear. Therefore, new approaches to elucidate the pathophysiology are needed. In the previous study, we generated liver organoids from different stages of NASH model mice that could recapitulate the part of NASH pathology. In the present study, we investigated the relationship between mitochondrial function and NASH disease by comparing NASH liver organoids (NLO) and control liver organoids (CLO). Compared with CLO, mitochondrial and organoid morphology was abnormal in NLO, with increased expression of mitochondrial mitogen protein, DRP1, and mitochondria-derived reactive oxygen species (ROS) production. Treatment of NLO with a DPR1 inhibitor, Mdivi-1 resulted in the improvement of morphology and the decreased expression of fibrosis-related markers, Col1a1 and Acta2. In addition, treatment of NASH model mice with Mdivi-1 showed a decrease in fatty liver. Mdivi-1 treatment also prevented fibrosis and ROS production in the liver. These results indicate that NLO undergoes enhanced metabolism and abnormal mitochondrial morphology compared with CLO. It was also suggested that Mdivi-1 may be useful as a therapeutic agent to ameliorate NASH pathology.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
- Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - Kiwamu Tanabe
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Haru Yamamoto
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Yusuke Ishihara
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Maria Mochizuki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Amira Abugomaa
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
- Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
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Wong MS, Lo CYJ, Chen YL, Chen FY, Kuo CH, Chen JS, Pei D, Pitrone P, Wu CZ. Gamma-Glutamyltransferase Is a Predictor for Future Changes of Diabetogenic Factors in Aged Chinese-A Four-Year Follow-Up Study. J Clin Med 2023; 12:5606. [PMID: 37685672 PMCID: PMC10488810 DOI: 10.3390/jcm12175606] [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: 07/25/2023] [Revised: 08/15/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Glucose homeostasis in the body is determined by four diabetes factors (DFs): insulin resistance (IR), glucose effectiveness (GE), and the two phases of insulin secretion-first phase (FPIS) and second phase (SPIS). Previous research points to a correlation between elevated levels of gamma-glutamyl transferase (γGT) and an increased risk of type 2 diabetes. This study investigates the relationship between γGT and the four DFs in older Chinese individuals. This study involved 2644 men and 2598 women, all of whom were relatively healthy Chinese individuals aged 60 years or more. The DFs were calculated using formulas developed by our research, based on demographic data and factors related to metabolic syndrome. Pearson's correlation was utilized to assess the relationship between γGT and the four DFs. The findings suggested a positive correlation between γGT and IR, FPIS, and SPIS, but a negative correlation with GE in men. Among women, only SPIS and GE were significantly correlated with γGT. The factors showed varying degrees of correlation, listed in descending order as follows: GE, SPIS, FPIS, and IR. This study confirms a significant correlation between γGT and DFs in this population, highlighting the noteworthy role of GE.
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Affiliation(s)
- Man Sze Wong
- Department of Medicine, School of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (M.S.W.); (C.Y.J.L.); (D.P.)
| | - Chun Yen Jun Lo
- Department of Medicine, School of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (M.S.W.); (C.Y.J.L.); (D.P.)
| | - Yen-Lin Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 11490, Taiwan;
| | - Fang-Yu Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Fu Jen Catholic University Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (F.-Y.C.); (C.-H.K.)
| | - Chun-Heng Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Fu Jen Catholic University Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (F.-Y.C.); (C.-H.K.)
| | - Jin-Shuen Chen
- Kaohsiung Veterans General Hospital, Kaohsiung City 81362, Taiwan;
- Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City 80424, Taiwan
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City 11490, Taiwan
| | - Dee Pei
- Department of Medicine, School of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (M.S.W.); (C.Y.J.L.); (D.P.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Fu Jen Catholic University Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24352, Taiwan; (F.-Y.C.); (C.-H.K.)
| | - Pietro Pitrone
- Radiology Department, Papardo Hospital, 98100 Messina, Italy;
| | - Chung-Ze Wu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
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29
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Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
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Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
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30
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Zhang Y, Szramowski M, Sun S, Henderson GC. Combining albumin deficiency and acute exercise reduces hepatic lipid droplet size in mice. Lipids Health Dis 2023; 22:78. [PMID: 37344835 PMCID: PMC10286408 DOI: 10.1186/s12944-023-01845-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/08/2023] [Indexed: 06/23/2023] Open
Abstract
Hepatic lipid droplets (LDs) are implicated in ectopic lipid accumulation. The core of LDs, triacylglycerol (TAG), is synthesized from the esterification of fatty acids to a glycerol-3-phosphate (G-3-P) backbone. Albumin transports plasma free fatty acids, and previously albumin knockout (Alb-/-) mice were shown to exhibit lower hepatic TAG levels than wildtype (WT). Exercise is a beneficial strategy to alter hepatic metabolism, but its impacts on reducing hepatic lipids are far from satisfactory. The aim of this study was to investigate the combined effect of albumin deficiency and acute exercise on hepatic LDs. Eight-week-old male Alb-/- and WT mice were divided into sedentary and exercise groups. Exercised mice performed a 30-min high-intensity exercise bout. Results showed that sedentary Alb-/- mice had smaller hepatic LDs (P < 0.0001), associated with mitochondria, while WT mice exhibited larger LDs, surrounded by glycogen granules. Following acute exercise, hepatic LDs in Alb-/- mice reduced by 40% in size, while in WT increased by 14% (P < 0.0001). The maintenance of WT hepatic LDs was associated with elevated G-3-P level (P < 0.05), potentially derived from glycogen (R = -0.32, %change in glycogen versus LD content, P < 0.05). The reduction in Alb-/- mice LDs after exercise was possibly due to their low glycogen level. In conclusion, Alb-/- mice exhibited an enhanced capacity for reducing hepatic LD size and content in response to exercise. These findings suggest that modulating albumin's functions combined with exercise could be a potential strategy to reduce ectopic lipid deposition in the liver.
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Affiliation(s)
- Yi Zhang
- Department of Nutrition Science, Purdue University, 700 Mitch Daniels Blvd., West Lafayette, IN, 47907, USA
| | - Mirandia Szramowski
- Department of Nutrition Science, Purdue University, 700 Mitch Daniels Blvd., West Lafayette, IN, 47907, USA
| | - Shuhan Sun
- Department of Nutrition Science, Purdue University, 700 Mitch Daniels Blvd., West Lafayette, IN, 47907, USA
| | - Gregory C Henderson
- Department of Nutrition Science, Purdue University, 700 Mitch Daniels Blvd., West Lafayette, IN, 47907, USA.
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31
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Ikewaki N, Ikeue Y, Nagataki M, Kurosawa G, Dedeepiya VD, Rajmohan M, Vaddi S, Senthilkumar R, Preethy S, Abraham SJK. Beneficial effects of 1,3-1,6 β-glucans produced by Aureobasidium pullulans on non-esterified fatty acid levels in diabetic KKAy mice and their potential implications in metabolic dysregulation. J Diabetes Metab Disord 2023; 22:487-494. [PMID: 37255831 PMCID: PMC10225397 DOI: 10.1007/s40200-022-01170-5] [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: 02/14/2022] [Accepted: 11/30/2022] [Indexed: 06/01/2023]
Abstract
Objectives In this study, we used an obese and diabetic mouse model to compare two strains of Aureobasidium pullulans (AFO-202 and N-163) produced beta-glucans (β-glucans), which alleviate lipotoxicity. Methods Four groups of KK-Ay mice were used, with six subjects in each group. Group 1: sacrificed on day 0 for baseline values; Group 2: control (drinking water); Group 3: AFO-202 beta glucan-200 mg/kg/day; Group 4: N-163 beta glucan-300 mg/kg/day for 28 consecutive days. Results Group 4 (N-163) had the lowest non-esterified fatty acids (NEFA) levels and marginally decreased triglyceride levels compared to the other groups. There were no significant differences in blood glucose, hemoglobin A1c (HbA1c), triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels. N-163 β-glucans decreased NEFA levels after 28 days. Conclusion These results, although modest, warrant further in-depth research into lipotoxicity and associated inflammatory cascades in both healthy and diseased subjects for the prevention and management of metabolic dysregulation and associated diseases such as non-alcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Nobunao Ikewaki
- Department of Medical Life Science, Kyushu University of Health and Welfare, Nobeoka, Japan
- Institute of Immunology, Junsei Educational Institute, Nobeoka, Miyazaki Japan
| | | | | | - Gene Kurosawa
- Department of Academic Research Support Promotion Facility, Center for Research Promotion and Support, Fujita Health University, Aichi, Japan
- MabGenesis KK, Nagoya, Japan
| | | | - Mathaiyan Rajmohan
- Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | | | - Rajappa Senthilkumar
- Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | - Senthilkumar Preethy
- Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | - Samuel J. K. Abraham
- Sophy Inc., Kochi, Japan
- Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
- Centre for Advancing Clinical Research (CACR), University of Yamanashi - School of Medicine, Chuo, Japan
- Antony- Xavier Interdisciplinary Scholastics (AXIS), GN Corporation Co. Ltd., 3-8, Wakamatsu, Kofu, Yamanashi 400-0866 Japan
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32
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Zhang L, Wang Y, Sun Y, Zhang X. Intermittent Fasting and Physical Exercise for Preventing Metabolic Disorders through Interaction with Gut Microbiota: A Review. Nutrients 2023; 15:2277. [PMID: 37242160 PMCID: PMC10224556 DOI: 10.3390/nu15102277] [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: 04/24/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Metabolic disorders entail both health risks and economic burdens to our society. A considerable part of the cause of metabolic disorders is mediated by the gut microbiota. The gut microbial structure and function are susceptible to dietary patterns and host physiological activities. A sedentary lifestyle accompanied by unhealthy eating habits propels the release of harmful metabolites, which impair the intestinal barrier, thereby triggering a constant change in the immune system and biochemical signals. Noteworthy, healthy dietary interventions, such as intermittent fasting, coupled with regular physical exercise can improve several metabolic and inflammatory parameters, resulting in stronger beneficial actions for metabolic health. In this review, the current progress on how gut microbiota may link to the mechanistic basis of common metabolic disorders was discussed. We also highlight the independent and synergistic effects of fasting and exercise interventions on metabolic health and provide perspectives for preventing metabolic disorders.
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Affiliation(s)
- Li Zhang
- Department of Physical Education, China University of Mining and Technology, Beijing 100083, China; (L.Z.); (Y.W.)
| | - Yuanshang Wang
- Department of Physical Education, China University of Mining and Technology, Beijing 100083, China; (L.Z.); (Y.W.)
| | - Ying Sun
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China;
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China;
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Yang LJ, Zhou JZ, Zheng YF, Hu X, He ZY, Du LJ, Gu X, Huang XY, Li J, Li YQ, Pan LY, Zhang XX, Gu XJ. Association of non-alcoholic fatty liver disease with total testosterone in non-overweight/obese men with type 2 diabetes mellitus. J Endocrinol Invest 2023:10.1007/s40618-023-02006-6. [PMID: 36725809 DOI: 10.1007/s40618-023-02006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/04/2023] [Indexed: 02/03/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) is considered as both a vital risk factor and a consequence of type 2 diabetes mellitus (T2DM). Low total testosterone (TT) is common in men with T2DM, contributing to increased risks of metabolic diseases. This study aimed to investigate the association between TT levels and the prevalence of NAFLD in men with T2DM. METHODS In this cross-sectional study, 1005 men with T2DM were enrolled in National Metabolic Management Center (MMC) of First Affiliated Hospital of Wenzhou Medical University between January 2017 and August 2021. NAFLD was diagnosed using ultrasound as described by the Chinese Liver Disease Association. Overweight/obesity was defined as body mass index (BMI) ≥ 25 kg/m2 according to WHO BMI classifications. RESULTS Individuals without NAFLD had higher serum TT levels than those with NAFLD. After adjustments for potential confounding factors, the top tertile was significantly associated with lower prevalence of NAFLD compared with the bottom tertile of TT level [odds ratio (OR) 0.303, 95% confidence interval (CI) 0.281-0.713; P < 0.001]. The association between TT with NAFLD in individuals with normal weight (OR 0.175, 95% CI 0.098-0.315; P < 0.001) was stronger than in individuals with overweight/obesity (OR 0.509, 95% CI 0.267-0.971; P = 0.040). There was a significant interaction of TT with overweight/obesity (P for interaction = 0.018 for NAFLD). CONCLUSION Higher serum TT was significantly associated with a lower prevalence of NAFLD in men with T2DM. We found that the relationship of TT and NAFLD was stronger in individuals with non-overweight/obesity.
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Affiliation(s)
- L J Yang
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - J Z Zhou
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Y F Zheng
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - X Hu
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Z Y He
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - L J Du
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - X Gu
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - X Y Huang
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - J Li
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Y Q Li
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - L Y Pan
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - X X Zhang
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - X J Gu
- Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, Zhejiang Province, China.
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Kotlyarov S. Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:597-615. [PMID: 36742172 PMCID: PMC9896611 DOI: 10.3748/wjg.v29.i4.597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/10/2022] [Indexed: 01/20/2023] Open
Abstract
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia
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Hong J, Kim Y. Fatty Liver/Adipose Tissue Dual-Targeting Nanoparticles with Heme Oxygenase-1 Inducer for Amelioration of Obesity, Obesity-Induced Type 2 Diabetes, and Steatohepatitis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2203286. [PMID: 36209391 PMCID: PMC9685446 DOI: 10.1002/advs.202203286] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/15/2022] [Indexed: 05/28/2023]
Abstract
Persistent uptake of high-calorie diets induces the storage of excessive lipid in visceral adipose tissue. Lipids secreted from obese adipose tissue are accumulated in peripheral tissues such as the liver, pancreas, and muscle, and impair insulin sensitivity causing type 2 diabetes mellitus (T2DM). Furthermore, the accumulation of inflammatory cytokines and lipids in the liver induces apoptosis and fibrogenesis, and ultimately causes nonalcoholic steatohepatitis (NASH). To modulate obese tissue environments, it is challenged to selectively deliver inducers of heme oxygenase-1 (HO-1) to adipose tissue with the aid of a prohibitin targeting drug delivery system. Prohibitin binding peptide (PBP), an oligopeptide targeting prohibitin rich in adipose tissue, is conjugated on the surface of Hemin- or CoPP-loaded poly(lactide-co-glycolide) nanoparticles (PBP-NPs). PBP-NPs efficiently differentiate lipid storing white adipocytes into energy-generating brown adipocytes in T2DM and NASH models. In addition, PBP-NPs are found to target prohibitin overexpressed fatty liver in the NASH model and inhibit hepatic uptake of circulating lipids. Furthermore, PBP-NPs switch phenotypes of inflammatory macrophages in damaged organs and lower inflammation. Taken together, dual-targeted induction of HO-1 in fatty adipose and liver tissues is proven to be a promising therapeutic strategy to ameliorate obesity, insulin resistance, and steatohepatitis by lowering lipids and cytokines.
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Affiliation(s)
- Juhyeong Hong
- Department of BioengineeringInstitute for Bioengineering and Biopharmaceutical Research Hanyang UniversitySeoul04763South Korea
- Education and Research Group for Biopharmaceutical Innovation LeaderHanyang UniversitySeoul04763South Korea
| | - Yong‐Hee Kim
- Department of BioengineeringInstitute for Bioengineering and Biopharmaceutical Research Hanyang UniversitySeoul04763South Korea
- Education and Research Group for Biopharmaceutical Innovation LeaderHanyang UniversitySeoul04763South Korea
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36
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Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism. Molecules 2022; 27:molecules27217269. [PMID: 36364213 PMCID: PMC9655600 DOI: 10.3390/molecules27217269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Breast cancer (BC) is a serious global challenge, and depression is one of the risk factors and comorbidities of BC. Recently, the research on the comorbidity of BC and depression has focused on the dysfunction of the hypothalamic–pituitary–adrenal axis and the persistent stimulation of the inflammatory response. However, the further mechanisms for comorbidity remain unclear. Epoxide metabolism has been shown to have a regulatory function in the comorbid mechanism with scattered reports. Hence, this article reviews the role of epoxide metabolism in depression and BC. The comprehensive review discloses the imbalance in epoxide metabolism and its downstream effect shared by BC and depression, including overexpression of inflammation, upregulation of toxic diols, and disturbed lipid metabolism. These downstream effects are mainly involved in the construction of the breast malignancy microenvironment through liver regulation. This finding provides new clues on the mechanism of BC and depression comorbidity, suggesting in particular a potential relationship between the liver and BC, and provides potential evidence of comorbidity for subsequent studies on the pathological mechanism.
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Foguet-Romero E, Samarra I, Guirro M, Riu M, Joven J, Menendez JA, Canela N, DelPino-Rius A, Fernández-Arroyo S, Herrero P. Optimization of a GC-MS Injection-Port Derivatization Methodology to Enhance Metabolomics Analysis Throughput in Biological Samples. J Proteome Res 2022; 21:2555-2565. [PMID: 36180971 DOI: 10.1021/acs.jproteome.2c00119] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Advances in metabolomics analysis and data treatment increase the knowledge of complex biological systems. One of the most used methodologies is gas chromatography-mass spectrometry (GC-MS) due to its robustness, high separation efficiency, and reliable peak identification through curated databases. However, methodologies are not standardized, and the derivatization steps in GC-MS can introduce experimental errors and take considerable time, exposing the samples to degradation. Here, we propose the injection-port derivatization (IPD) methodology to increase the throughput in plasma metabolomics analysis by GC-MS. The IPD method was evaluated and optimized for different families of metabolites (organic acids, amino acids, fatty acids, sugars, sugar phosphates, etc.) in terms of residence time, injection-port temperature, and sample/derivatization reagent ratio. Finally, the method's usefulness was validated in a study consisting of a cohort of obese patients with or without nonalcoholic steatohepatitis. Our results show a fast, reproducible, precise, and reliable method for the analysis of biological samples by GC-MS. Raw data are publicly available at MetaboLights with Study Identifier MTBLS5151.
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Affiliation(s)
- Elisabet Foguet-Romero
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Iris Samarra
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Maria Guirro
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Marc Riu
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Jorge Joven
- Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, 43201 Reus, Spain.,Institut d'investigació Sanitària Pere Virgili, Hospital Universitari de Sant Joan, Unitat de Recerca Biomèdica, 43204 Reus, Spain
| | - Javier A Menendez
- Girona Biomedical Research Institute (IdIBGi), Salt, 17190 Girona, Spain.,Metabolism & Cancer Group, ProCURE, Catalan Institute of Oncology, 17007 Girona, Spain
| | - Núria Canela
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Antoni DelPino-Rius
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Salvador Fernández-Arroyo
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
| | - Pol Herrero
- Centre for Omic Sciences (Joint Unit Eurecat─Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Eurecat, Centre Tecnològic de Catalunya, Avda. De la Universitat, 1, 43204 Reus, Tarragona, Spain
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Briand F, Sencio V, Robil C, Heumel S, Deruyter L, Machelart A, Barthelemy J, Bogard G, Hoffmann E, Infanti F, Domenig O, Chabrat A, Richard V, Prévot V, Nogueiras R, Wolowczuk I, Pinet F, Sulpice T, Trottein F. Diet-Induced Obesity and NASH Impair Disease Recovery in SARS-CoV-2-Infected Golden Hamsters. Viruses 2022; 14:v14092067. [PMID: 36146875 PMCID: PMC9503118 DOI: 10.3390/v14092067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/08/2023] Open
Abstract
Obese patients with non-alcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. There is an urgent need for new treatments that lower the severity of COVID-19 in this vulnerable population. To better replicate the human context, we set up a diet-induced model of obesity associated with dyslipidemia and NASH in the golden hamster (known to be a relevant preclinical model of COVID-19). A 20-week, free-choice diet induces obesity, dyslipidemia, and NASH (liver inflammation and fibrosis) in golden hamsters. Obese NASH hamsters have higher blood and pulmonary levels of inflammatory cytokines. In the early stages of a SARS-CoV-2 infection, the lung viral load and inflammation levels were similar in lean hamsters and obese NASH hamsters. However, obese NASH hamsters showed worse recovery (i.e., less resolution of lung inflammation 10 days post-infection (dpi) and lower body weight recovery on dpi 25). Obese NASH hamsters also exhibited higher levels of pulmonary fibrosis on dpi 25. Unlike lean animals, obese NASH hamsters infected with SARS-CoV-2 presented long-lasting dyslipidemia and systemic inflammation. Relative to lean controls, obese NASH hamsters had lower serum levels of angiotensin-converting enzyme 2 activity and higher serum levels of angiotensin II—a component known to favor inflammation and fibrosis. Even though the SARS-CoV-2 infection resulted in early weight loss and incomplete body weight recovery, obese NASH hamsters showed sustained liver steatosis, inflammation, hepatocyte ballooning, and marked liver fibrosis on dpi 25. We conclude that diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected hamsters. This model might be of value for characterizing the pathophysiologic mechanisms of COVID-19 and evaluating the efficacy of treatments for the severe forms of COVID-19 observed in obese patients with NASH.
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Affiliation(s)
| | - Valentin Sencio
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Cyril Robil
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Séverine Heumel
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Lucie Deruyter
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Arnaud Machelart
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Johanna Barthelemy
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Gemma Bogard
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Eik Hoffmann
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | | | | | | | | | - Vincent Prévot
- Univ. Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European Genomic Institute for Diabetes (EGID), F-59000 Lille, France
| | - Ruben Nogueiras
- Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), S-15781 Santiago de Compostela, Spain
| | - Isabelle Wolowczuk
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Florence Pinet
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, F-59000 Lille, France
| | | | - François Trottein
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
- Correspondence:
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Seo SH, Lee DH, Lee YS, Cho KJ, Park HJ, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Bae SH, Kim SU. Co-administration of ursodeoxycholic acid with rosuvastatin/ezetimibe in a non-alcoholic fatty liver disease model. Gastroenterol Rep (Oxf) 2022; 10:goac037. [PMID: 35982712 PMCID: PMC9379373 DOI: 10.1093/gastro/goac037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 07/08/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
Background Ursodeoxycholic acid (UDCA), statins, and ezetimibe (EZE) have demonstrated beneficial effects against non-alcoholic fatty liver disease (NAFLD). We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin (RSV)/EZE in the treatment of NAFLD. Methods NAFLD mouse models were developed by injecting thioacetamide, fasting, and high-carbohydrate refeeding, high-fat diet, and choline-deficient L-amino acid-defined high-fat diet (CDAHFD). Low-dose UDCA (L-UDCA; 15 mg/kg) or high-dose UDCA (H-UDCA; 30 mg/kg) was administered with RSV/EZE. We also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 cells. Results Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation, serum alanine aminotransferase (ALT) levels, and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice (all P < 0.01). In addition, in the group fasted and refed with a high-carbohydrate diet, UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group (all P < 0.05). Subsequently, H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1 (SCD-1) mRNA levels (P = 0.027) in the liver of high-fat diet-fed mice compared with those observed in the vehicle group. In the CDAHFD-fed mouse model, UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group (all P < 0.05). In addition, UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells (all P < 0.05). Conclusion Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression.
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Affiliation(s)
- Sang Hyun Seo
- Department of Internal Medicine, Graduate School of Medicine Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Hyun Lee
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Seol Lee
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyung Joo Cho
- Department of Internal Medicine, Graduate School of Medicine Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Jung Park
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Hye Won Lee
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Jun Yong Park
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Do Young Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Soo Han Bae
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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Ng C, Lee KL, Muthiah MD, Wu KX, Chioh FWJ, Tan K, Soon GST, Shabbir A, Loo WM, Low ZS, Chen Q, Tan NS, Ng HH, Dan YY, Cheung C. Endothelial‐immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease. EMBO Rep 2022; 23:e54271. [PMID: 35403791 PMCID: PMC9171677 DOI: 10.15252/embr.202154271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, mechanisms of NAFLD‐associated vasculopathy remain understudied. Here, we show that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. In mouse models of diet‐induced NAFLD, we confirm heightened endothelial expressions of CXCL12 in the aortas and the liver vasculatures, and increased retention of infiltrated leukocytes within the vessel walls. To elucidate endothelial‐immune crosstalk, we performed immunoprofiling by single‐cell analysis, uncovering T cell intensification in NAFLD patients. Functionally, treatment with a CXCL12‐neutralizing antibody is effective at moderating the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8+ T lymphocytes. Interference with the CXCL12‐CXCR4 axis using a CXCR4 antagonist also averts the impact of immune cell transendothelial migration and restores endothelial barrier integrity. Clinically, we detect threefold more circulating damaged endothelial cells in NAFLD patients than in healthy controls. Our work provides insight into the modulation of interactions with effector immune cells to mitigate endothelial injury in NAFLD.
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Affiliation(s)
- Chun‐Yi Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Khang Leng Lee
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Kan Xing Wu
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Konstanze Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Asim Shabbir
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Surgery University Surgical Cluster National University Health System Singapore Singapore
| | - Wai Mun Loo
- Department of Medicine National University Health System Singapore Singapore
| | - Zun Siong Low
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
| | - Huck Hui Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
- Genome Institute of Singapore Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
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Wang Y, Chen C, Chen J, Sang T, Peng H, Lin X, Zhao Q, Chen S, Eling T, Wang X. Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation. Redox Biol 2022; 52:102322. [PMID: 35504134 PMCID: PMC9079118 DOI: 10.1016/j.redox.2022.102322] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/10/2022] [Accepted: 04/23/2022] [Indexed: 02/08/2023] Open
Abstract
Mitochondrial dysfunction and oxidative stress-mediated inflammasome activation play critical roles in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1), or growth differentiation factor-15 (GDF15), is associated with many biological processes and diseases, including NAFLD. However, the role of NAG-1/GDF15 in regulating oxidative stress and whether this process is associated with absent in melanoma 2 (AIM2) inflammasome activation in NAFLD are unknown. In this study, we revealed that NAG-1/GDF15 is significantly downregulated in liver tissues of patients with steatosis compared to normal livers using the Gene Expression Omnibus (GEO) database, and in free fatty acids (FFA, oleic acid/palmitic acid, 2:1)-induced HepG2 and Huh-7 cellular steatosis models. Overexpression of NAG-1/GDF15 in transgenic (Tg) mice significantly alleviated HFD-induced obesity and hepatic steatosis, improved lipid homeostasis, enhanced fatty acid β-oxidation and lipolysis, inhibited fatty acid synthesis and uptake, and inhibited AIM2 inflammasome activation and the secretion of IL-18 and IL-1β, as compared to their wild-type (WT) littermates without reducing food intake. Furthermore, NAG-1/GDF15 overexpression attenuated FFA-induced triglyceride (TG) accumulation, lipid metabolism deregulation, and AIM2 inflammasome activation in hepatic steatotic cells, while knockdown of NAG-1/GDF15 demonstrated opposite effects. Moreover, NAG-1/GDF15 overexpression inhibited HFD- and FFA-induced oxidative stress and mitochondrial damage which in turn reduced double-strand DNA (dsDNA) release into the cytosol, while NAG-1/GDF15 siRNA showed opposite effects. The reduced ROS production and dsDNA release may be responsible for attenuated AIM2 activation by NAG-1/GDF15 upon fatty acid overload. In conclusion, our results provide evidence that other than regulating lipid homeostasis, NAG-1/GDF15 protects against hepatic steatosis through a novel mechanism via suppressing oxidative stress, mitochondrial damage, dsDNA release, and AIM2 inflammasome activation.
NAG-1/GDF15 is downregulated in human steatotic liver and FFA-induced liver cells. NAG-1/GDF15 inhibits hepatic steatosis and improves lipid homeostasis. AIM2 inflammasome is activated in steatosis models and is inhibited by NAG-1/GDF15. NAG-1/GDF15 reduces oxidative stress and mitochondrial damage in steatosis models. NAG-1/GDF15 inhibits mitochondrial dsDNA release and thus inhibits AIM2 activation.
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Siemienowicz KJ, Filis P, Thomas J, Fowler PA, Duncan WC, Rae MT. Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of “PCOS Males”. Biomedicines 2022; 10:biomedicines10061291. [PMID: 35740312 PMCID: PMC9220073 DOI: 10.3390/biomedicines10061291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 12/04/2022] Open
Abstract
First-degree male relatives of polycystic ovary syndrome (PCOS) sufferers can develop metabolic abnormalities evidenced by elevated circulating cholesterol and triglycerides, suggestive of a male PCOS equivalent. Similarly, male sheep overexposed to excess androgens in fetal life develop dyslipidaemia in adolescence. Dyslipidaemia, altered lipid metabolism, and dysfunctional hepatic mitochondria are associated with the development of non-alcoholic liver disease (NAFLD). We therefore dissected hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly administered to male ovine fetuses to create prenatal androgenic overexposure. Liver RNA sequencing and proteomics occurred at 6 months of age. Hepatic lipids, glycogen, ATP, reactive oxygen species (ROS), DNA damage, and collagen were assessed. Adolescent PA males had an increased accumulation of hepatic cholesterol and glycogen, together with perturbed glucose and fatty acid metabolism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phosphorylation and ATP synthesis, and impaired mitophagy. Mitochondrial dysfunction in PA males was associated with increased hepatic ROS level and signs of early liver fibrosis, with clinical relevance to NAFLD progression. We conclude that excess in utero androgen exposure in male fetuses leads to a PCOS-like metabolic phenotype with dysregulated mitochondrial function and likely lifelong health sequelae.
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Affiliation(s)
- Katarzyna J. Siemienowicz
- School of Applied Science, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (J.T.); (M.T.R.)
- MRC Centre for Reproductive Health, The University of Edinburgh, Edinburgh EH16 4TJ, UK;
- Correspondence:
| | - Panagiotis Filis
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (P.F.); (P.A.F.)
| | - Jennifer Thomas
- School of Applied Science, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (J.T.); (M.T.R.)
| | - Paul A. Fowler
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (P.F.); (P.A.F.)
| | - W. Colin Duncan
- MRC Centre for Reproductive Health, The University of Edinburgh, Edinburgh EH16 4TJ, UK;
| | - Mick T. Rae
- School of Applied Science, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (J.T.); (M.T.R.)
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Santos LLM, Diniz MDFHS, Goulart AC, Barreto SM, Figueiredo RC. Association between neck circumference and non-alcoholic fatty liver disease: cross-sectional analysis from ELSA-Brasil. SAO PAULO MED J 2022; 140:213-221. [PMID: 35043830 PMCID: PMC9610241 DOI: 10.1590/1516-3180.2021.0095.r2.22062021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/22/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become a public health problem worldwide. Neck circumference (NC) is a simple anthropometric adiposity parameter that has been correlated with cardiometabolic disorders like NAFLD. OBJECTIVES To investigate the association between NC and NAFLD, considering their obesity-modifying effect, among participants from the Longitudinal Study of Adult Health (ELSA-Brasil) baseline study. DESIGN AND SETTINGS Cross-sectional study at the ELSA-Brasil centers of six public research institutions. METHODS This analysis was conducted on 5,187 women and 4,270 men of mean age 51.8 (± 9.2) years. Anthropometric indexes (NC, waist circumference [WC] and body mass index [BMI]), biochemical and clinical parameters (diabetes, hypertension and dyslipidemia) and hepatic ultrasound were measured. The association between NC and NAFLD was estimated using multinomial logistic regression, considering potential confounding effects (age, WC, diabetes, hypertension and dyslipidemia). Effect modification was investigated by including the interaction term NC x BMI in the final model. RESULTS The frequency of NAFLD and mean value of NC were 33.6% and 33.9 (± 2.5) cm in women, and 45.8% and 39.4 (± 2.8) cm in men, respectively. Even after all adjustments, larger NC was associated with a greater chance of moderate/severe NAFLD (1.16; 95% confidence interval [CI] for women; 1.05, 95% CI for men; P < 0.001). Presence of multiplicative interaction between NC and BMI (P < 0.001) was also observed. CONCLUSION NC was positively associated with NAFLD in both sexes, regardless of traditional adiposity indexes such as BMI and WC. The magnitude of the association was more pronounced among women.
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Affiliation(s)
| | | | - Alessandra Carvalho Goulart
- MD, PhD. Clinical Epidemiologist and Researcher, Center of Clinical and Epidemiological Research, Hospital Universitário, Universidade de São Paulo (HU-USP), São Paulo (SP), Brazil.
| | - Sandhi Maria Barreto
- MD, PhD. Professor, Medical School and Clinical Hospital, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte (MG), Brazil.
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Cadamuro M, Lasagni A, Sarcognato S, Guido M, Fabris R, Strazzabosco M, Strain AJ, Simioni P, Villa E, Fabris L. The Neglected Role of Bile Duct Epithelial Cells in NASH. Semin Liver Dis 2022; 42:34-47. [PMID: 34794182 DOI: 10.1055/s-0041-1739455] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and affects 25% of the population in Western countries. NAFLD is the hepatic manifestation of the metabolic syndrome, linked to insulin resistance, which is the common pathogenetic mechanism. In approximately 40% of NAFLD patients, steatosis is associated with necro-inflammation and fibrosis, resulting in nonalcoholic steatohepatitis (NASH), a severe condition that may progress to cirrhosis and liver cancer. Although the hepatocyte represents the main target of the disease, involvement of the bile ducts occurs in a subset of patients with NASH, and is characterized by ductular reaction and activation of the progenitor cell compartment, which incites portal fibrosis and disease progression. We aim to dissect the multiple biological effects that adipokines and metabolic alterations exert on cholangiocytes to derive novel information on the mechanisms driven by insulin resistance, which promote fibro-inflammation and carcinogenesis in NASH.
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Affiliation(s)
| | - Alberto Lasagni
- Division of General Medicine, Padua University-Hospital, Padua, Italy
| | | | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Roberto Fabris
- Division of Clinica Medica 3, Center for the Study and the Integrated Management of Obesity, Padua University-Hospital, Padua, Italy
| | - Mario Strazzabosco
- Department of Internal Medicine, Digestive Disease Section, Liver Center, Yale University, New Haven, Connecticut
| | - Alastair J Strain
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Paolo Simioni
- Division of General Medicine, Padua University-Hospital, Padua, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Erica Villa
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, Modena, Italy
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Division of General Medicine, Padua University-Hospital, Padua, Italy.,Department of Internal Medicine, Digestive Disease Section, Liver Center, Yale University, New Haven, Connecticut
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Kotlyarov S, Bulgakov A. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease. Cells 2021; 10:2978. [PMID: 34831201 PMCID: PMC8616072 DOI: 10.3390/cells10112978] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia;
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Urso CJ, Zhou H. Role of CD36 in Palmitic Acid Lipotoxicity in Neuro-2a Neuroblastoma Cells. Biomolecules 2021; 11:1567. [PMID: 34827565 PMCID: PMC8615720 DOI: 10.3390/biom11111567] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 01/21/2023] Open
Abstract
Elevated level of palmitic acid (PA), a long-chain saturated fatty acid (SFA), is lipotoxic to many different types of cells including Neuro-2a (N2a) neuroblastoma cells. CD36 is a multifunctional membrane glycoprotein that acts as a fatty acid translocase (FAT) facilitating the transport of long-chain free fatty acids (FFAs) into cells, serves a fatty acid (FA) sensing function in areas including taste buds and the proximal gut, and acts as a scavenger receptor that binds to many ligands, including FAs, collagen, oxidized low-density lipoproteins, and anionic phospholipids. However, the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells remains unclear. In this study, we examined FA uptake in BSA- and PA-treated N2a cells and investigated the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells. Our data showed that PA treatment promoted FA uptake in N2a cells, and that treatment with sulfo-N-succinimidyl oleate (SSO), a CD36 inhibitor, significantly decreased FA uptake in BSA- and PA-treated N2a cells, and ameliorated PA-induced decrease of cell viability, decrease of diploid cells, and increase of tetraploid cells. We also found that CD36 knockdown significantly decreased FA uptake in both BSA- and PA-treated cells as compared to their corresponding wild-type controls, and dramatically attenuated PA-induced cell cycle defects in N2a cells. Our data suggest that CD36 may play a critical role in FA uptake and PA lipotoxicity in N2a cells. CD36 may therefore represent a regulatory target against pathologies caused by excess FAs.
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Affiliation(s)
| | - Heping Zhou
- Department of Biological Sciences, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA;
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Xu Q. Human Three-Dimensional Hepatic Models: Cell Type Variety and Corresponding Applications. Front Bioeng Biotechnol 2021; 9:730008. [PMID: 34631680 PMCID: PMC8497968 DOI: 10.3389/fbioe.2021.730008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/30/2021] [Indexed: 12/23/2022] Open
Abstract
Owing to retained hepatic phenotypes and functions, human three-dimensional (3D) hepatic models established with diverse hepatic cell types are thought to recoup the gaps in drug development and disease modeling limited by a conventional two-dimensional (2D) cell culture system and species-specific variability in drug metabolizing enzymes and transporters. Primary human hepatocytes, human hepatic cancer cell lines, and human stem cell-derived hepatocyte-like cells are three main hepatic cell types used in current models and exhibit divergent hepatic phenotypes. Primary human hepatocytes derived from healthy hepatic parenchyma resemble in vivo-like genetic and metabolic profiling. Human hepatic cancer cell lines are unlimitedly reproducible and tumorigenic. Stem cell-derived hepatocyte-like cells derived from patients are promising to retain the donor's genetic background. It has been suggested in some studies that unique properties of cell types endue them with benefits in different research fields of in vitro 3D modeling paradigm. For instance, the primary human hepatocyte was thought to be the gold standard for hepatotoxicity study, and stem cell-derived hepatocyte-like cells have taken a main role in personalized medicine and regenerative medicine. However, the comprehensive review focuses on the hepatic cell type variety, and corresponding applications in 3D models are sparse. Therefore, this review summarizes the characteristics of different cell types and discusses opportunities of different cell types in drug development, liver disease modeling, and liver transplantation.
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Affiliation(s)
- Qianqian Xu
- School of Chinese Medicine, and Centre for Cancer and Inflammation Research, Hong Kong Baptist University, Hong Kong, China
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Huang CH, Huang YL, Shen ZQ, Lin CH, Tsai TF. Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice. Biomedicines 2021; 9:biomedicines9091229. [PMID: 34572415 PMCID: PMC8470730 DOI: 10.3390/biomedicines9091229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/06/2021] [Accepted: 09/12/2021] [Indexed: 12/21/2022] Open
Abstract
Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Chen-Hua Huang
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-H.H.); (Y.-L.H.); (Z.-Q.S.)
| | - Yi-Long Huang
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-H.H.); (Y.-L.H.); (Z.-Q.S.)
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Zhao-Qing Shen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-H.H.); (Y.-L.H.); (Z.-Q.S.)
| | - Chao-Hsiung Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-H.H.); (Y.-L.H.); (Z.-Q.S.)
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: (C.-H.L.); (T.-F.T.); Tel.: +886-2-2826-67280 (C.-H.L.); +886-2-2826-67293 (T.-F.T.)
| | - Ting-Fen Tsai
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (C.-H.H.); (Y.-L.H.); (Z.-Q.S.)
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Taiwan
- Correspondence: (C.-H.L.); (T.-F.T.); Tel.: +886-2-2826-67280 (C.-H.L.); +886-2-2826-67293 (T.-F.T.)
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Babu AF, Csader S, Lok J, Gómez-Gallego C, Hanhineva K, El-Nezami H, Schwab U. Positive Effects of Exercise Intervention without Weight Loss and Dietary Changes in NAFLD-Related Clinical Parameters: A Systematic Review and Meta-Analysis. Nutrients 2021; 13:nu13093135. [PMID: 34579012 PMCID: PMC8466505 DOI: 10.3390/nu13093135] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/05/2021] [Accepted: 09/05/2021] [Indexed: 12/13/2022] Open
Abstract
One of the focuses of non-alcoholic fatty liver disease (NAFLD) treatment is exercise. Randomized controlled trials investigating the effects of exercise without dietary changes on NAFLD-related clinical parameters (liver parameters, lipid metabolism, glucose metabolism, gut microbiota, and metabolites) were screened using the PubMed, Scopus, Web of Science, and Cochrane databases on 13 February 2020. Meta-analyses were performed on 10 studies with 316 individuals who had NAFLD across three exercise regimens: aerobic exercise, resistance training, and a combination of both. No studies investigating the role of gut microbiota and exercise in NAFLD were found. A quality assessment via the (RoB)2 tool was conducted and potential publication bias, statistical outliers, and influential cases were identified. Overall, exercise without significant weight loss significantly reduced the intrahepatic lipid (IHL) content (SMD: −0.76, 95% CI: −1.04, −0.48) and concentrations of alanine aminotransaminase (ALT) (SMD: −0.52, 95% CI: −0.90, −0.14), aspartate aminotransaminase (AST) (SMD: −0.68, 95% CI: −1.21, −0.15), low-density lipoprotein cholesterol (SMD: −0.34, 95% CI: −0.66, −0.02), and triglycerides (TG) (SMD: −0.59, 95% CI: −1.16, −0.02). The concentrations of high-density lipoprotein cholesterol, total cholesterol (TC), fasting glucose, fasting insulin, and glycated hemoglobin were non-significantly altered. Aerobic exercise alone significantly reduced IHL, ALT, and AST; resistance training alone significantly reduced TC and TG; a combination of both exercise types significantly reduced IHL. To conclude, exercise overall likely had a beneficial effect on alleviating NAFLD without significant weight loss. The study was registered at PROSPERO: CRD42020221168 and funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 813781.
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Affiliation(s)
- Ambrin Farizah Babu
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
- Afekta Technologies Ltd., Yliopistonranta 1L, 70211 Kuopio, Finland
| | - Susanne Csader
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
| | - Johnson Lok
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
| | - Carlos Gómez-Gallego
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
| | - Kati Hanhineva
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
- Afekta Technologies Ltd., Yliopistonranta 1L, 70211 Kuopio, Finland
- Department of Life Technologies, Food Chemistry and Food Development Unit, University of Turku, 20500 Turku, Finland
| | - Hani El-Nezami
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Ursula Schwab
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; (A.F.B.); (S.C.); (J.L.); (C.G.-G.); (K.H.); (H.E.-N.)
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70210 Kuopio, Finland
- Correspondence: ; Tel.: +358-403552791
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Rodrigues RM, He Y, Hwang S, Bertola A, Mackowiak B, Ahmed YA, Seo W, Ma J, Wang X, Park SH, Guan Y, Fu Y, Vanhaecke T, Feng D, Gao B. E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9. Cell Mol Gastroenterol Hepatol 2021; 13:151-171. [PMID: 34390865 PMCID: PMC8593619 DOI: 10.1016/j.jcmgh.2021.08.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/04/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH. METHODS A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus-Cxcl1 overexpression (HFD+AdCxcl1). Genetic deletion of E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model. RESULTS By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD+AdCxcl1 mice. The HFD+AdCxcl1-induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD+AdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice. CONCLUSIONS E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.
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Affiliation(s)
- Robim M. Rodrigues
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland,Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Adeline Bertola
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Jing Ma
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Seol Hee Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland,Correspondence Address correspondence to: Bin Gao, MD, PhD, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892. fax: (301) 480-0257.
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