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Sookoian S, Pirola CJ, Sanyal AJ. MASLD as a non-communicable disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01039-x. [PMID: 39905174 DOI: 10.1038/s41575-025-01039-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Affiliation(s)
- Silvia Sookoian
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
- Clinical and Molecular Hepatology, Translational Research in Health Center (CENITRES), Maimónides University, Buenos Aires, Argentina.
| | - Carlos J Pirola
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Systems Biology of Complex Diseases, Translational Research in Health Center (CENITRES), Maimónides University, Buenos Aires, Argentina
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Modanwal S, Mishra A, Mishra N. An integrative analysis of GEO data to identify possible therapeutic biomarkers of prostate cancer and targeting potential protein through Zea mays phytochemicals by virtual screening approaches. J Biomol Struct Dyn 2025; 43:709-729. [PMID: 38217083 DOI: 10.1080/07391102.2023.2283163] [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: 08/01/2023] [Accepted: 11/08/2023] [Indexed: 01/14/2024]
Abstract
Prostate cancer (PC) is a prevalent type of cancer among men. Delaying the treatment of patients with upgraded or upstaged cancer may lead to unmanageable circumstances. The aim of this study is to contribute to the finding of biomarkers that are specific to PC and identify drug candidates derived from plants. The information about cancer is critical for clinicians to make decisions about patient treatment in the era of precision medicine. Advances in genomics technology have opened up new possibilities for identifying genes that are associated with cancer, including PC. This study identifies novel differentially expressed genes for PC. The seven PC microarray datasets were selected from the National Center for Biotechnology Information (NCBI)/Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were found based on a fold change of |logFC| ≥ 1 and an adjusted p-value of <0.05. The DEGs were further studied using several bioinformatics tools, including STRING, CytoHubba, SRplot, Coremine Medical database, FunRich and GeneMANIA, cBioPortal. The six new potential biomarkers, GAGE2A, GAGE12G, GAGE2E, GAGE13, GAGE12F and CSAG1 were identified. These biomarkers are associated with biological processes (BPs) such as cell division, and gene expression regulation, so these genes may have a crucial role in PC progression and may serve as potential biomarkers for PC. A total of 497 phytochemicals from corn plants have been screened against the target protein and found LTS0176591 as the best lead molecule with docking score of -6.31 kcal/mol. Further, molecular mechanics-generalized born surface area (MM-GBSA), molecular dynamics simulation, principal component analysis (PCA), free energy landscape (FEL) and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) were carried out to validate the findings.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shristi Modanwal
- Department of Applied Science, Indian Institute of Information Technology Allahabad, Prayagraj, India
| | - Ashutosh Mishra
- Department of Applied Science, Indian Institute of Information Technology Allahabad, Prayagraj, India
| | - Nidhi Mishra
- Department of Applied Science, Indian Institute of Information Technology Allahabad, Prayagraj, India
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Bhardwaj M, Mazumder PM. An insight on the additive impact of type 2 diabetes mellitus and nonalcoholic fatty liver disease on cardiovascular consequences. Mol Biol Rep 2025; 52:169. [PMID: 39873861 DOI: 10.1007/s11033-025-10249-0] [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: 04/29/2024] [Accepted: 01/10/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are associated with a multifactorial complicated aetiology that is often coexisting and has a strong and distinct connection with cardiovascular diseases (CVDs). In order to accomplish effective and appropriate therapeutic strategies, a deeper understanding of the bidirectional interaction between NAFLD patients, NAFLD patients with T2DM, and NAFLD patients with CVDs is required to control the concomitant rise in prevalence of these conditions worldwide. This article also aims to shed light on the epidemiology and mechanisms behind the relationship between T2DM, NAFLD and the related cardiovascular consequences. METHOD Literature was collected from PubMed, Medline, Embase, Web of Science and Google scholar from inception to June, 2024. For surveying literature different combinations and formats of terms including NAFLD, NASH, T2DM and CVDs were used. RESULTS In the recent decade, clinical and epidemiological studies have been conducted and provide strong evidence that NAFLD is closely linked with CVD progression along with associated morbidity and mortality in both patients with and without T2DM. Several mechanistic approaches contribute to cardiovascular consequences and abnormalities in cardiac biomarkers in T2DM and NAFLD patients, including adipose tissue malfunction, mitochondrial dysfunction, the microbiota, genetic and epigenetic alterations contributing to insulin resistance, glucotoxicity and lipotoxicity. CONCLUSION The study reveals a complex interplay between diabetes, hepatic and cardiovascular complications, leading to significant morbidity and mortality in diabetic and NAFLD patients. This pandemic necessitates further research to identify mitigating variables and develop effective treatment approaches.
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Affiliation(s)
- Monika Bhardwaj
- Department of Pharmaceutical Sciences & Technology, BIT Mesra, Ranchi, 835215, India
| | - Papiya Mitra Mazumder
- Department of Pharmaceutical Sciences & Technology, BIT Mesra, Ranchi, 835215, India.
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Byeon H. Insights from exploring the interrelated dynamics of gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease. World J Gastroenterol 2024; 30:4977-4982. [PMID: 39679311 PMCID: PMC11612707 DOI: 10.3748/wjg.v30.i46.4977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/21/2024] Open
Abstract
This article delved into the comprehensive study by Jiang et al, which meticulously examined the bidirectional relationships among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease through a multicenter study, systematic review, and meta-analysis. The study provides significant evidence supporting these associations, offering valuable insights into the etiology and potential prevention strategies for these interconnected conditions. The clinical significance of these bidirectional relationships is profound, as they underscore the importance of recognizing these conditions not only as isolated diseases but as part of a complex network that can influence each other. These results highlight the critical need for thorough screening and personalized prevention strategies for individuals with these interconnected conditions. Explicit implications for prevention strategies and early screening practices are crucial, as they can lead to early detection and intervention, significantly altering disease progression and outcomes. Furthermore, identifying potential therapeutic targets within these shared pathways may enhance treatment efficacy and patient outcomes, making this research highly relevant to clinical practice. By comprehending the common pathophysiological mechanisms and applying specific interventions, healthcare professionals can greatly enhance patient care and lessen the impact of these widespread diseases on global health.
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Affiliation(s)
- Haewon Byeon
- Department of Digital Anti-aging Healthcare (BK21), Inje University, Gimhae 50834, South Korea
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Baker LA, Minor KM, Tate N, Furrow E. Whole blood gene expression analysis of spontaneous hypertriglyceridemia in dogs suggests an underlying pro-thrombotic process. PLoS One 2024; 19:e0313343. [PMID: 39531449 PMCID: PMC11556679 DOI: 10.1371/journal.pone.0313343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Hypertriglyceridemia (HTG) is influenced by multiple genetic and environmental factors. Spontaneous, idiopathic HTG is common in the Miniature Schnauzer dog and presumed to have a strong genetic influence in this breed. To define genes that are differentially expressed in dogs with HTG, we performed RNA sequencing on peripheral blood of 13 Miniature Schnauzers with HTG and 18 controls. We identified 110 differentially expressed genes (DEGs). Pathway analysis suggests an ongoing pro-thrombotic, endothelial activation process in dogs with HTG. The gene with the largest fold change (5.4 ± 1.4, Padj = 4.4E-04), SERPINE1, encodes plasminogen activator inhibitor 1 (PAI-1), a known risk factor for atherosclerosis and thrombosis. Other top DEGs, including SHANK3, MMRN1, and FZD7, are involved in endothelial activation. Two of the top DEGs, ARHGAP29 and ARHGAP21, inhibit pro-thrombotic pathways and are potentially protective of disease sequelae. Top DEGs, including SERPINE1 and ARHGAP21, have also been linked to metabolic syndrome or its features (e.g. insulin resistance) in humans and animal models. Our findings indicate that HTG in the Miniature Schnauzer dog has similar features to HTG and metabolic syndrome in humans, highlighting the potential use of the dog as a spontaneous model for further research into the etiology and effects of HTG.
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Affiliation(s)
- Lauren A. Baker
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Katie M. Minor
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Nicole Tate
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Eva Furrow
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America
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Yang Z, Chen Z, Wang J, Li Y, Zhang H, Xiang Y, Zhang Y, Shao Z, Wu P, Lu D, Lin H, Tong Z, Liu J, Dong Q. Multiple Machine Learning Identifies Key Gene PHLDA1 Suppressing NAFLD Progression. Inflammation 2024:10.1007/s10753-024-02164-6. [PMID: 39496918 DOI: 10.1007/s10753-024-02164-6] [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: 05/15/2024] [Revised: 10/04/2024] [Accepted: 10/12/2024] [Indexed: 11/06/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) poses a serious global health threat, with its progression mechanisms not yet fully understood. While several molecular markers for NAFLD have been developed in recent years, a lack of robust evidence hampers their clinical application. Therefore, identifying novel and potent biomarkers would directly aid in the prediction, prevention, and personalized treatment of NAFLD. We downloaded NAFLD-related datasets from the Gene Expression Omnibus (GEO). Differential expression analysis and functional analysis were initially conducted. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) and multiple machine learning strategies were employed to screen and identify key genes, and the diagnostic value was assessed using Receiver Operating Characteristic (ROC) analysis. We then explored the relationship between genes and immune cells using transcriptome data and single-cell RNA sequencing (scRNA-seq) data. Finally, we validated our findings in cell and mouse NAFLD models. We obtained 23 overlapping differentially expressed genes (DEGs) across three NAFLD datasets. Enrichment analysis revealed that DEGs were associated with Apoptosis, Parathyroid hormone synthesis, secretion and action, Colorectal cancer, p53 signaling pathway, and Biosynthesis of unsaturated fatty acids. After employing machine learning strategies, we identified one gene, pleckstrin homology like domain family A member 1 (PHLDA1), downregulated in NAFLD and showing high diagnostic accuracy. CIBERSORT analysis revealed significant associations of PHLDA1 with various immune cells. Single-cell data analysis demonstrated downregulation of PHLDA1 in NAFLD, with PHLDA1 exhibiting a significant negative correlation with macrophages. Furthermore, we found PHLDA1 to be downregulated in an in vitro hepatic steatosis cell model, and overexpression of PHLDA1 significantly reduced lipid accumulation, as well as the expression of key molecules involved in hepatic lipogenesis and fatty acid uptake, such as FASN, SCD-1, and CD36. Additionally, gene set enrichment analysis (GSEA) pathway enrichment analysis suggested that PHLDA1 may influence NAFLD progression through pathways such as Cytokine Cytokine Receptor Interaction, Ecm Receptor Interaction, Parkinson's Disease, and Ribosome pathways. Our conclusions were further validated in a mouse model of NAFLD. Our study reveals that PHLDA1 inhibits the progression of NAFLD, as overexpression of PHLDA1 significantly reduces lipid accumulation in cells and markedly decreases the expression of key molecules involved in liver lipogenesis and fatty acid uptake. Therefore, PHLDA1 may emerge as a novel potential target for future prediction, diagnosis, and targeted prevention of NAFLD.
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Affiliation(s)
- Zhenwei Yang
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China.
| | - Zhiqin Chen
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, China
| | - Jingchao Wang
- Department of Biochemistry and Molecular Biology, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Shenzhen University School of Medicine, Shenzhen, China
| | - Yizhang Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hailin Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yu Xiang
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Yuwei Zhang
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Zhaozhao Shao
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Pei Wu
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Ding Lu
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Huajiang Lin
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Zhaowei Tong
- Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, 313000, China
| | - Jiang Liu
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
| | - Quan Dong
- Department of Gastroenterology, The Fifth School of Clinical Medicine of Zhejiang, Huzhou Central Hospital, Chinese Medical University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang Province, 313000, People's Republic of China
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Kathirvel E, Morgan K, Malysheva OV, Caudill MA, Morgan TR. Betaine for the prevention and treatment of insulin resistance and fatty liver in a high-fat dietary model of insulin resistance in C57BL mice. Front Nutr 2024; 11:1409972. [PMID: 39119463 PMCID: PMC11307150 DOI: 10.3389/fnut.2024.1409972] [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: 03/31/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
Aim The aim was to investigate mechanisms by which betaine improves hepatic insulin signaling in a dietary mouse model of insulin resistance and fatty liver. Methods C57BL 6J mice were fed a standard diet (SF), a standard diet with betaine (SFB), a nutritionally complete high fat (HF) diet, or a high fat diet with betaine (HFB) for 14 weeks. In a separate experiment, mice were fed high fat diet for 18 weeks, half of whom received betaine for the final 4 weeks. Activation of insulin signaling in the liver was assessed by western blot. Insulin signaling was also assessed in insulin resistant primary human hepatocytes treated with betaine. Results As compared with SF, mice receiving HF diet were heavier, had more hepatic steatosis, and abnormal glucose tolerance test (GTT). Betaine content in liver and serum was 50% lower in HF than in SF; betaine supplementation restored serum and liver betaine content. Betaine treatment of HF reduced whole body insulin resistance as measured by GTT. Betaine treatment of HF increased tyrosine phosphorylation of insulin receptor substrate-1 and phosphorylation (activation) of Akt, and increased hepatic glycogen content. In vitro, betaine reversed insulin resistance in primary human hepatocytes by increasing insulin-stimulated tyrosine phosphorylation of IRS1 and of Akt. Conclusion Betaine supplementation reduced whole body insulin resistance and increased activation of insulin signaling pathways in the liver in a mouse model of insulin resistance and fatty liver created by feeding a nutritionally complete high fat diet for 14 weeks. Betaine also reduced liver injury as assessed by ALT and by liver histology. In vitro, betaine reversed insulin resistance by increasing insulin-stimulated tyrosine phosphorylation of IRS1 and activation of downstream proteins in the insulin signaling cascade in insulin resistant primary human hepatocytes.
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Affiliation(s)
- Elango Kathirvel
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
| | - Kengathevy Morgan
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
| | - Olga V. Malysheva
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
| | - Marie A. Caudill
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
| | - Timothy R. Morgan
- Research Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
- Department of Medicine, University of California, Irvine, Irvine, CA, United States
- Medical Healthcare Group, Veterans Administration Healthcare System, Long Beach, CA, United States
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AkbariRad M, Pezeshki Rad M, Nobakht H, Moodi Ghalibaf A, Firoozi A, Torshizian A, Bina AR, Beheshti Namdar A, Sadeghi M. Prevalence, characteristics, and risk factors of non-alcoholic fatty liver disease in North East of Iran: a population-based study. BMC Gastroenterol 2024; 24:212. [PMID: 38926664 PMCID: PMC11210030 DOI: 10.1186/s12876-024-03302-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/20/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common dietary disorder caused by fatty changes in the liver parenchyma and hepatocytes without alcohol consumption. The present study aimed to investigate the prevalence, characteristics, and risk factors of NAFLD in the Mashhad Persian Cohort Study population. METHOD The present population-based cross-sectional study included all PERSIAN Organizational Cohort study in Mashhad University of Medical Sciences (POCM), Mashhad, Iran by census sampling method. Eligible participants were divided into two groups due to their NAFLD condition (NAFLD positive or NAFLD negative). All enrolled participants were evaluated based on their clinical aspects, anthropometric measures, laboratory tests, and ultrasound features. Statistical analysis was conducted using SPSS software version 16 (SPSS Inc., Chicago, USA -version 16). A P-value less than 0.05 was considered as the significance level. RESULTS A total of 1198 individuals were included in the study, of which 638 (53.3%) were male and the rest were female. The mean age of the participants was 46.89 ± 8.98 years. A total of 246 patients (20.53%) were NAFLD positive, of which 122 (49.59%) were in grade 1, 112 (45.52%) were in grade 2, and 12 (4.87%) were in grade 3. The prevalence of fatty liver was significantly higher in males than in females (p < 0.001). There were significant differences between NAFLD positive and NAFLD negative participants in terms of having a history of hypertension (P = 0.044), body mass index (P < 0.001), body fat percentage (P = 0.001), waist circumference (P < 0.001), liver craniocaudal length (P = 0.012), fasting blood sugar (FBS) (P = 0.047), aspartate aminotransferase (AST) (P = 0.007), and alanine aminotransferase (ALT) (P = 0.001). Further analysis revealed a strong significant association between BMI, previous history of hypertension, higher levels of serum ALT, and NAFLD (P < 0.05). CONCLUSION It can be concluded that ultrasound findings accompanied by laboratory AST and ALT level enzymes could be a cost-benefit approach for NAFLD early diagnosis. The craniocaudal size of the liver could be a beneficent marker for estimating the severity of the disease; however, more studies are recommended to evaluate this variable for future practice against the issue.
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Affiliation(s)
- Mina AkbariRad
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Pezeshki Rad
- Department of Radiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hadi Nobakht
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Ashkan Torshizian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Reza Bina
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Masoumeh Sadeghi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Epidemiology, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran.
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Xiao H, Tang D, Zheng C, Yang Z, Zhao W, Guo S. Atypical dynamic network reconfiguration and genetic mechanisms in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2024; 132:110957. [PMID: 38365102 DOI: 10.1016/j.pnpbp.2024.110957] [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: 08/06/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND Brain dynamics underlie complex forms of flexible cognition or the ability to shift between different mental modes. However, the precise dynamic reconfiguration based on multi-layer network analysis and the genetic mechanisms of major depressive disorder (MDD) remains unclear. METHODS Resting-state functional magnetic resonance imaging (fMRI) data were acquired from the REST-meta-MDD consortium, including 555 patients with MDD and 536 healthy controls (HC). A time-varying multi-layer network was constructed, and dynamic modular characteristics were used to investigate the network reconfiguration. Additionally, partial least squares regression analysis was performed using transcriptional data provided by the Allen Human Brain Atlas (AHBA) to identify genes associated with atypical dynamic network reconfiguration in MDD. RESULTS In comparison to HC, patients with MDD exhibited lower global and local recruitment coefficients. The local reduction was particularly evident in the salience and subcortical networks. Spatial transcriptome correlation analysis revealed an association between gene expression profiles and atypical dynamic network reconfiguration observed in MDD. Further functional enrichment analyses indicated that positively weighted reconfiguration-related genes were primarily associated with metabolic and biosynthetic pathways. Additionally, negatively enriched genes were predominantly related to programmed cell death-related terms. CONCLUSIONS Our findings offer robust evidence of the atypical dynamic reconfiguration in patients with MDD from a novel perspective. These results offer valuable insights for further exploration into the mechanisms underlying MDD.
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Affiliation(s)
- Hairong Xiao
- MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University, Changsha 410006, China
| | - Dier Tang
- School of Mathematics, Jilin University, Changchun 130015, China
| | - Chuchu Zheng
- MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University, Changsha 410006, China
| | - Zeyu Yang
- MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University, Changsha 410006, China
| | - Wei Zhao
- MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University, Changsha 410006, China; Key Laboratory of Applied Statistics and Data Science, Hunan Normal University, College of Hunan Province, Changsha 410006, China
| | - Shuixia Guo
- MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University, Changsha 410006, China; Key Laboratory of Applied Statistics and Data Science, Hunan Normal University, College of Hunan Province, Changsha 410006, China.
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Mohammadpour-Asl S, Roshan-Milani B, Roshan-Milani S, Saboory E, Ghobadian B, Chodari L. Endoplasmic reticulum stress PERK-ATF4-CHOP pathway is involved in non-alcoholic fatty liver disease in type 1 diabetic rats: The rescue effect of treatment exercise and insulin-like growth factor I. Heliyon 2024; 10:e27225. [PMID: 38468961 PMCID: PMC10926145 DOI: 10.1016/j.heliyon.2024.e27225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Abstract
Endoplasmic Reticulum Stress (ERS) is a key factor in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) in diabetes. The current study aimed to examine the effects of exercise and IGF-I on ERS markers in liver tissue. Rats were divided into five groups (n = 8 per group), including control (CON), diabetes (DIA), diabetes + exercise (DIA + EX), diabetes + IGF-I (DIA + IGF-I), and diabetes + exercise + IGF-I (DIA + EX + IGF-I). Type 1 diabetes was induced by an I.P. injection of streptozotocin (60 mg/kg). After 30 days of treatment with exercise or IGF-I alone or in combination, liver tissue was assessed for caspase 12, 8, and CHOP protein levels, and expression of ERS markers (ATF-6, PERK, IRE-1A) and lipid metabolism-involved genes (FAS, FXR, SREBP-1c) by western immunoblotting. In addition, for the evaluation of histopathological changes in the liver, Hematoxylin - Eosin and Masson's Trichrome staining were done. Compared to the control group, diabetes significantly caused liver fibrosis, induced ERS, increased caspase 12 and 8 levels in the liver, and changed expression levels of genes associated with lipid metabolism, including FAS, FXR, and SREBP-1c. Treatment with either exercise or IGF-I reduced fibrosis levels suppressed ER stress markers and apoptosis, and improved expression of genes associated with lipid metabolism. In addition, simultaneous treatment with exercise and IGF-I showed a synergistic effect compared to DIA + E and DIA + IGF-I. The results suggest that IGF-1 and exercise reduced liver fibrosis possibly by reducing ERS, creating adaptive ER stress status, and improving protein folding.
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Affiliation(s)
- Shadi Mohammadpour-Asl
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Shiva Roshan-Milani
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Ehsan Saboory
- Department of Addiction Studies, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Bijan Ghobadian
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Leila Chodari
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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Sookoian S, Pirola CJ. The serum uric acid/creatinine ratio is associated with nonalcoholic fatty liver disease in the general population. J Physiol Biochem 2023; 79:891-899. [PMID: 35546386 DOI: 10.1007/s13105-022-00893-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022]
Abstract
Serum uric acid-to-creatinine ratio (sUA/CrR) may be associated with metabolic syndrome components, but limited evidence exists on a relationship between sUA/Cr and NAFLD. Here, we investigated the association between sUA/CrR and NAFLD.We performed a cross-sectional analysis in 3359 subjects who participated in the NHANES 2017-2018 survey and consumed less than 30 and 20 g alcohol (men and women, respectively), with no positive tests of viral hepatitis. Liver steatosis was defined by controlled attenuation parameter and fibrosis by stiffness measurements obtained via transient elastography. We modeled the relationship between NAFLD and relevant demographic, anthropometric, and biochemical variables.sUA/CrR was significantly higher in participants with NAFLD than those without NAFLD. LASSO logit regression showed that only logarithmized age (p = 1.2e-3), waist circumference (WC) (p = 1.8e-5), triglycerides (p = 5e-6), and sUA/CrR (p = 3e-5) were retained in the model. Multivariate logistic analysis demonstrated a significant association between sUA/CrR and NAFLD; the OR for NAFLD of one log(sUA/CrR) increase was 2.61 (95% CI: 1.86-3.68, p < 3e-8) after adjusting for relevant covariables, including aminotransaminase levels and the effect of sUA/CrR remained significant for highest WC quintiles. The model's predictive power with vs. without sUA/CrR was slightly but significantly better (Auroc: 0.859 ± 0.006 vs. 0.855 ± 0.007, p < 1.1e-2). Mediation analysis showed that SUA/CrR modestly mediates the effect of WC and insulin resistance but not glycohemoglobin on NAFLD.In conclusion, elevated sUA/CrR was significantly associated with NAFLD in the general population. Therefore, kidney function should be closely monitored in NAFLD patients.
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Affiliation(s)
- Silvia Sookoian
- Facultad de Medicina, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
- Instituto de Investigaciones Médicas (IDIM), Unidad de Biología de Sistemas de Enfermedades Complejas, Departamento de Hepatología Clínica Y Molecular, Consejo Nacional de Investigaciones Científicas Y Técnicas-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
| | - Carlos J Pirola
- Facultad de Medicina, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
- Instituto de Investigaciones Médicas (IDIM), Unidad de Biología de Sistemas de Enfermedades Complejas, Departamento de Genética Y Biología Molecular de Enfermedades Complejas, Consejo Nacional de Investigaciones Científicas Y Técnicas-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
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12
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Xing Y, Gao X, Li Q, Li X, Wang Y, Yang Y, Yang S, Lau PWC, Zeng Q, Wang H. Associations between exposure to ambient particulate matter and advanced liver fibrosis in Chinese MAFLD patients. JOURNAL OF HAZARDOUS MATERIALS 2023; 460:132501. [PMID: 37690203 DOI: 10.1016/j.jhazmat.2023.132501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/16/2023] [Accepted: 09/05/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND & AIMS Liver fibrosis is an important feature in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). This study aimed to explore the association between long-term ambient particulate matter (PM) exposure and advanced liver fibrosis (ALF) in MAFLD participants. METHODS A cross-sectional study of 23170 adults recruited from 33 provinces of China from 2010 to 2020. ALF was detected using the nonalcoholic fatty liver disease fibrosis score (NFS). The annual average levels of particulate matter with aerodynamic diameters of ≤ 1 µm (PM1), ≤ 2.5 µm (PM2.5) and ≤ 10 µm (PM10) were calculated using validated spatiotemporal models. Generalized additive models were applied to analyze the association between PM and ALF in patients with MAFLD. RESULTS One-year exposure to higher levels of all PM was found to increase the risk of ALF, with odds ratios (ORs) of 1.10 (95% CI 1.06-1.14), 1.05 (1.03-1.07), and 1.03(1.02-1.04) for each 10 μg/m3 increase in PM1, PM2.5 and PM10, respectively. With the dissection of the impact of PM1 in PM2.5, PM2.5 in PM10 and PM1 in PM10, we found that PM2.5 had a stronger impact on ALF (both Pinteraction＜0.05) in comparison with PM1 and PM10. CONCLUSIONS Long-term exposure to PM is associated with ALF in patients with MAFLD, with PM2.5 playing a dominant role.
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Affiliation(s)
- Yunfei Xing
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Xiangyang Gao
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China
| | - Qin Li
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100083, China
| | - Xueying Li
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Youxin Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Yifan Yang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Shuhan Yang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Patrick W C Lau
- Department of Sport, Physical Education and Health, Hong Kong Baptist University, 999077, Hong Kong SAR China; Laboratory of Exercise Science and Health, BNU-HKBU United International College, Zhuhai 519087, China
| | - Qiang Zeng
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100039, China.
| | - Hui Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China.
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Pirola CJ, Sookoian S. Non-alcoholic fatty liver disease mediates the effect of obesity on arterial hypertension. Liver Int 2023; 43:2167-2176. [PMID: 37312639 DOI: 10.1111/liv.15643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND It has been consistently shown that obesity contributes directly to arterial hypertension and cardiovascular disease (CVD), independently of other risk factors. Likewise, non-alcoholic fatty liver disease (NAFLD) is acknowledged as a contributor and a risk enhancer for CVD. OBJECTIVES We tested the hypothesis of a causal role of NAFLD in the effect of obesity on arterial hypertension. METHODS Using causal mediation analysis, we quantified the magnitude of the body mass index (BMI) effect on arterial hypertension and CV-traits mediated by NAFLD. First, we analysed data from 1348 young adults in the Bogalusa Heart Study (BHS), a cohort aimed at assessing the natural history of CVD. Then, we used data from 3359 participants of the National Health and Nutrition Examination Survey (2017-2018 cycle, NHANES) to replicate the findings. RESULTS We found that roughly 92% of the effects of BMI on arterial hypertension in the BHS and 51% in the NHANES population are mediated by NAFLD. In addition, indirect effects of BMI on systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) through NAFLD explained up to 91%, 93%, and 100% of the total effect, respectively, in the BHS. In the NHANES survey, indirect effects of BMI through NAFLD on CV traits explain a significant proportion of the total effects (SBP = 60.4%, HR = 100%, and pulse pressure = 88%). CONCLUSION NAFLD mediates a substantial proportion of the effect of obesity on the presence of hypertension and CV-parameters independently of relevant covariates. This conclusion has implications for clinical management.
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Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Universidad Maimónides, Buenos Aires, Argentina
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14
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James A, Wang K, Wang Y. Therapeutic Activity of Green Tea Epigallocatechin-3-Gallate on Metabolic Diseases and Non-Alcoholic Fatty Liver Diseases: The Current Updates. Nutrients 2023; 15:3022. [PMID: 37447347 DOI: 10.3390/nu15133022] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Green tea polyphenols have numerous functions including antioxidation and modulation of various cellular proteins and are thus beneficial against metabolic diseases including obesity, type 2 diabetes, cardiovascular and non-alcoholic fatty liver diseases, and their comorbidities. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea and is attributed to antioxidant and free radical scavenging activities, and the likelihood of targeting multiple metabolic pathways. It has been shown to exhibit anti-obesity, anti-inflammatory, anti-diabetic, anti-arteriosclerotic, and weight-reducing effects in humans. Worldwide, the incidences of metabolic diseases have been escalating across all age groups in modern society. Therefore, EGCG is being increasingly investigated to address the problems. This review presents the current updates on the effects of EGCG on metabolic diseases, and highlights evidence related to its safety. Collectively, this review brings more evidence for therapeutic application and further studies on EGCG and its derivatives to alleviate metabolic diseases and non-alcoholic fatty liver diseases.
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Affiliation(s)
- Armachius James
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, Beijing Technology and Business University, Beijing 100048, China
- Tanzania Agricultural Research Institute (TARI), Makutupora Center, Dodoma P.O. Box 1676, Tanzania
| | - Ke Wang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, Beijing Technology and Business University, Beijing 100048, China
- Rizhao Huawei Institute of Comprehensive Health Industries, Shandong Keepfit Biotech. Co., Ltd., Rizhao 276800, China
| | - Yousheng Wang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, Beijing Technology and Business University, Beijing 100048, China
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15
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Pirola CJ, Sookoian S. Editorial: NAFLD, chronic kidney disease, and pleiotropy-Why is PNPLA3 omnipresent? Aliment Pharmacol Ther 2023; 57:1180-1182. [PMID: 37094315 DOI: 10.1111/apt.17491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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16
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Pirola CJ, Sookoian S. Advances in our understanding of the molecular heterogeneity of fatty liver disease: toward informed treatment decision making. Expert Rev Gastroenterol Hepatol 2023; 17:317-324. [PMID: 36912694 DOI: 10.1080/17474124.2023.2191190] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
INTRODUCTION nonalcoholic fatty liver disease (NAFLD) is a complex disorder resulting from intricate relationships with diverse cardiometabolic risk factors and environmental factors. NAFLD may result in severe chronic liver damage and potentially declining liver function. AREAS COVERED Accumulated knowledge over the last decade indicates that the disease trajectory presents substantial heterogeneity. In addition, overlapping features with the diseases of the metabolic syndrome, combined with heterogeneity in disease mechanisms, further complicates NAFLD diagnosis and prognosis, and hampers progress in biomarker and pharmacological discoveries. Here, we explore solving the heterogeneous clinical landscape of NAFLD by cluster analysis of molecular signatures that serve as a proxy for disease stratification into molecular sub-types. First, we collected information on NAFLD and metabolic syndrome-associated protein-coding genes by data mining the literature. Next, we performed pathways enrichment and cluster analyses to decipher and dissect the different patterns of phenotypic heterogeneity. Our approach showed unique biological pathways for every clinical subtype/group, namely NAFLD + obesity, NAFLD + arterial hypertension, NAFLD + dyslipidemia, and NAFLD + type 2 diabetes. EXPERT OPINION Patients with NAFLD may be benefited by a better understanding of the disease biology, which involves 'dissection' of the molecular sub-phenotypes that drive the disease progression.
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Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Altos Estudios En Ciencias Humanas Y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Buenos Aires, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios En Ciencias Humanas Y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Buenos Aires, Argentina
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17
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Milbank E, Díaz-Trelles R, Dragano N, Latorre J, Mukthavaram R, Mayneris-Perxachs J, Ortega F, Federici M, Burcelin R, Karmali PP, Tachikawa K, Chivukula P, López M, Fernández-Real JM, Moreno-Navarrete JM. Liver lipopolysaccharide binding protein prevents hepatic inflammation in physiological and pathological non-obesogenic conditions. Pharmacol Res 2023; 187:106562. [PMID: 36410673 DOI: 10.1016/j.phrs.2022.106562] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/09/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022]
Abstract
Lipopolysaccharide binding protein (LBP) knockout mice models are protected against the deleterious effects of major acute inflammation but its possible physiological role has been less well studied. We aimed to evaluate the impact of liver LBP downregulation (using nanoparticles containing siRNA- Lbp) on liver steatosis, inflammation and fibrosis during a standard chow diet (STD), and in pathological non-obesogenic conditions, under a methionine and choline deficient diet (MCD, 5 weeks). Under STD, liver Lbp gene knockdown led to a significant increase in gene expression markers of liver inflammation (Itgax, Tlr4, Ccr2, Ccl2 and Tnf), liver injury (Krt18 and Crp), fibrosis (Col4a1, Col1a2 and Tgfb1), endoplasmic reticulum (ER) stress (Atf6, Hspa5 and Eif2ak3) and protein carbonyl levels. As expected, the MCD increased hepatocyte vacuolation, liver inflammation and fibrosis markers, also increasing liver Lbp mRNA. In this model, liver Lbp gene knockdown resulted in a pronounced worsening of the markers of liver inflammation (also including CD68 and MPO activity), fibrosis, ER stress and protein carbonyl levels, all indicative of non-alcoholic steatohepatitis (NASH) progression. At cellular level, Lbp gene knockdown also increased expression of the proinflammatory mediators (Il6, Ccl2), and markers of fibrosis (Col1a1, Tgfb1) and protein carbonyl levels. In agreement with these findings, liver LBP mRNA in humans positively correlated with markers of liver damage (circulating hsCRP, ALT activity, liver CRP and KRT18 gene expression), and with a network of genes involved in liver inflammation, innate and adaptive immune system, endoplasmic reticulum stress and neutrophil degranulation (all with q-value<0.05). In conclusion, current findings suggest that a significant downregulation in liver LBP levels promotes liver oxidative stress and inflammation, aggravating NASH progression, in physiological and pathological non-obesogenic conditions.
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Affiliation(s)
- Edward Milbank
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | | | - Nathalia Dragano
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Jèssica Latorre
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain
| | | | - Jordi Mayneris-Perxachs
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain
| | - Francisco Ortega
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, Rome, Italy
| | - Remy Burcelin
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université Paul Sabatier, Toulouse, France
| | | | | | | | - Miguel López
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - José Manuel Fernández-Real
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; Department of Medicine, University of Girona, Girona, Spain.
| | - José María Moreno-Navarrete
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), and Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; Department of Medicine, University of Girona, Girona, Spain.
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18
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Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease. J Hepatol 2023; 78:191-206. [PMID: 36063967 DOI: 10.1016/j.jhep.2022.08.030] [Citation(s) in RCA: 126] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/04/2022] [Accepted: 08/19/2022] [Indexed: 02/01/2023]
Abstract
Alcohol use and metabolic syndrome are highly prevalent in the population and frequently co-exist. Both are implicated in a large range of health problems, including chronic liver disease, hepatocellular carcinoma, and liver-related outcomes (i.e. decompensation or liver transplantation). Studies have yielded mixed results regarding the effects of mild-moderate alcohol consumption on the risk of metabolic syndrome and fatty liver disease, possibly due to methodological differences. The few available prospective studies have indicated that mild-moderate alcohol use is associated with an increase in liver-related outcomes. This conclusion was substantiated by systems biology analyses suggesting that alcohol and metabolic syndrome may play a similar role in fatty liver disease, potentiating an already existing dysregulation of common vital homeostatic pathways. Alcohol and metabolic factors are independently and jointly associated with liver-related outcomes. Indeed, metabolic syndrome increases the risk of liver-related outcomes, regardless of alcohol intake. Moreover, the components of metabolic syndrome appear to have additive effects when it comes to the risk of liver-related outcomes. A number of population studies have implied that measures of central/abdominal obesity, such as the waist-to-hip ratio, can predict liver-related outcomes more accurately than BMI, including in individuals who consume harmful quantities of alcohol. Many studies even point to synergistic interactions between harmful alcohol use and many metabolic components. This accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease highlights the multifactorial background of liver disease in the population. The available evidence suggests that more holistic approaches could be useful for risk prediction, diagnostics and treatment planning.
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19
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Huang DQ, Downes M, Evans RM, Witztum JL, Glass CK, Loomba R. Shared Mechanisms between Cardiovascular Disease and NAFLD. Semin Liver Dis 2022; 42:455-464. [PMID: 36008083 PMCID: PMC9828940 DOI: 10.1055/a-1930-6658] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid artery atherosclerosis. Individuals with NAFLD are at a substantially higher risk of fatal and nonfatal cardiovascular events. NAFLD and cardiovascular disease share multiple common disease mechanisms, such as systemic inflammation, insulin resistance, genetic risk variants, and gut microbial dysbiosis. In this review, we discuss the epidemiology of cardiovascular disease in NAFLD, and highlight common risk factors. In addition, we examine recent advances evaluating the shared disease mechanisms between NAFLD and cardiovascular disease. In conclusion, multidisciplinary collaborations are required to further our understanding of the complex relationship between NAFLD and cardiovascular disease and potentially identify therapeutic targets.
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Affiliation(s)
- Daniel Q. Huang
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Ronald M. Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Joseph L. Witztum
- Division of Endocrinology and Metabolism, Department of Medicine, University California San Diego, San Diego, California
| | - Christopher K. Glass
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California
- Department of Medicine, University of California San Diego, San Diego, California
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, California
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20
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Michalak A, Guz M, Kozicka J, Cybulski M, Jeleniewicz W, Lach T, Cichoż-Lach H. Red blood cell distribution width derivatives in alcohol-related liver cirrhosis and metabolic-associated fatty liver disease. World J Gastroenterol 2022; 28:5636-5647. [PMID: 36304090 PMCID: PMC9594007 DOI: 10.3748/wjg.v28.i38.5636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/07/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Looking for undiscovered blood markers of liver fibrosis and steatosis still remains an issue worth exploring. There are still plenty of unresolved issues related to the actual role of hematological indices as potential markers of liver function. AIM To study red blood cell distribution width (RDW), RDW-to-platelet ratio (RPR) and RDW-to-lymphocyte ratio (RLR) in alcohol-related liver cirrhosis (ALC) and metabolic-associated fatty liver disease (MAFLD). METHODS The study group was composed of 302 people: 142 patients with ALC and 92 with MAFLD; 68 persons were included as controls. RDW, RPR and RLR were measured in each person. Indirect and direct parameters of liver fibrosis were also assessed [aspartate transaminase to alkaline transaminase ratio, aspartate transaminase to platelet ratio index (APRI), fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio (GPR), procollagen I carboxyterminal propeptide, procollagen III aminoterminal propeptide, transforming growth factor-α, platelet-derived growth factor AB, laminin]. MELD score in ALC patients and non-alcoholic fatty liver disease (NAFLD) fibrosis score together with BARD score were obtained in the MAFLD group. The achieved results were compared to controls. Then a correlation between assessed markers was done. Diagnostic value of each investigated parameter and its suggested cut-off in the research group were evaluated with area under the curve (AUC). RESULTS RDW, RPR and RLR values turned out to be significantly higher in ALC and MAFLD groups compared to controls (ALC: P < 0.0001; NAFLD: P < 0.05, P < 0.0001 and P < 0.0001, respectively). RPR correlated positively with MELD score (P < 0.01) and indirect indices of liver fibrosis (FIB-4 and GPR; P < 0.0001) in ALC patients; negative correlations were found between PDGF-AB and both: RDW and RPR (P < 0.01 and P < 0.0001, respectively). RPR correlated positively with NAFLD fibrosis score and APRI (P < 0.0001) in the MAFLD group; a positive relationship was observed between RDW and FIB-4, too (P < 0.05). AUC values and suggested cut-offs for RDW, RPR and RLR in ALC patients were: 0.912 (> 14.2%), 0.965 (> 0.075) and 0.914 (> 8.684), respectively. AUC values and suggested cut-offs for RDW, RPR and RLR in MAFLD patients were: 0.606 (> 12.8%), 0.724 (> 0.047) and 0.691 (> 6.25), respectively. CONCLUSION RDW with its derivatives appear to be valuable diagnostic markers in patients with ALC. They can also be associated with a deterioration of liver function in this group.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology, Medical University of Lublin, Lublin 20-954, Poland
| | - Małgorzata Guz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland
| | - Joanna Kozicka
- Department of Gastroenterology, Medical University of Lublin, Lublin 20-954, Poland
| | - Marek Cybulski
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland
| | - Witold Jeleniewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Lublin 20-954, Poland
| | - Halina Cichoż-Lach
- Department of Gastroenterology, Medical University of Lublin, Lublin 20-954, Poland
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Zeng Y, Jing X, Wu C, Xie Y, Chen L, Chen Y, Li H, Hong D, Cai X. Is Helicobacter pylori infection the risk factor of metabolic associated fatty liver disease：A cross-sectional study.. [DOI: 10.21203/rs.3.rs-2005721/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Abstract
Background: Recently, with new diagnosis criteria, metabolic associated fatty liver disease (MAFLD) was introduced to replace the diagnosis of nonalcoholic fatty liver disease (NAFLD). Considering that there weren’t sufficient studies on MAFLD in China, we aimed to explore the relationship between MAFLD and H. pylori infection, as well as the potential risk factors of MAFLD.Methods: In this cross-sectional study, 3449 subjects were enrolled from a Hospital Health Management Center of Shantou in China between July 2020 and October 2021. All participants included had underwent blood test, 13C urea breath test (13C-UBT) and abdominal ultrasound examination. The association between H. pylori infection and MAFLD were analyzed using logistic regression. Machine learning approach were applied to explore independent risk factors of MAFLD.Results: The overall prevalence of MAFLD was 39.4% in our study population. Of a total of 3449 participants, MAFLD was diagnosed in 1043 of 2254 males (46.3%) and 315 of 1195 females (26.4%). The prevalence of MAFLD increased with age and peaked at the 60-69-year age group (overall participants: 58.8%; male: 56.2%; female: 64.0%), and then declined slightly in the 70-above-year age group. The result of multivariable logistic regression revealed that H. pylori infection was not significantly correlated with MAFLD. Using logistic regression and LASSO regression, we identified age, overweight/obesity, T2DM, hypertension, UA, TG, HDL and ALT as independent risk factors of MAFLD.Conclusions: The prevalence of MAFLD in Shantou of south China was relatively high, and the prevalence was higher in males than in females. Our results showed that H. pylori infection wasn’t associated with the risk of MAFLD, when age, overweight/obesity, T2DM, hypertension, UA, TG, HDL and ALT were independent risk factors of MAFLD.
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Affiliation(s)
- Yicheng Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Xubin Jing
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Chaofen Wu
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yanchun Xie
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Lingzi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Haopeng Li
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Danmian Hong
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Xianbin Cai
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
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22
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Monjes NM, Wagner PM, Guido ME. “Disruption of the molecular clock severely affects lipid metabolism in a Hepatocellular Carcinoma Cell model”. J Biol Chem 2022; 298:102551. [DOI: 10.1016/j.jbc.2022.102551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 11/26/2022] Open
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Liang C, Yu Z, Bai L, Hou W, Tang S, Zhang W, Chen X, Hu Z, Duan Z, Zheng S. Association of Serum Bilirubin With Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2022; 13:869579. [PMID: 35937795 PMCID: PMC9346511 DOI: 10.3389/fendo.2022.869579] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) are the leading chronic diseases worldwide. There are still many controversies about the association between serum bilirubin and MetS or NAFLD. This study aims to evaluate the association of serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL) with MetS and NAFLD. METHODS Multiple databases were searched for relevant studies until November 2021. Randomized controlled trials, cross-sectional and cohort studies evaluating the association between serum bilirubin levels and MetS or NAFLD were included. RESULTS Twenty-four cross-sectional and cohort studies with 101, 517 participants were finally analyzed. Fifteen studies and 6 studies evaluated the association between bilirubin and MetS or NAFLD in health screening population, respectively, while 3 studies evaluated the association between bilirubin and non-alcoholic steatohepatitis (NASH) in NAFLD patients. Random effect model analysis showed the inverse association between TBIL and MetS in male (95%CI=0.71-0.96) and gender-neutral (95%CI=0.61-0.91) group. However, no significant association was found in females. Notably, the inverse association between DBIL and MetS was noticed in male (95%CI=0.36-0.75), female (95%CI=0.16-0.58) and gender-neutral population (95%CI=0.67-0.92). IBIL level was inversely associated with MetS in females (95%CI=0.52-0.96), whereas no statistical correlation presented in males. TBIL was not statistically correlated with NAFLD in gender-neutral or male subgroup. Similarly, there were no association between DBIL or IBIL and NAFLD in gender-neutral subgroup. However, the negative correlation between DBIL and NAFLD existed in males (95%CI=0.76-0.96). In NAFLD patients, IBIL analysis showed an inverse association with NASH (95%CI=0.01-0.12). CONCLUSION Serum TBIL and DBIL levels, especially DBIL levels, assume an inverse correlation with MetS in healthy population. Serum IBIL is inversely associated with the onset and degree of NASH in NAFLD patients. Exogenous bilirubin supplement may be a potential strategy to assist in lowering the risk of developing MetS and NAFLD. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier CRD42021293349.
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Affiliation(s)
- Chen Liang
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Zhiyuan Yu
- School of Medicine, Nankai University, Tianjin, China
- Department of General Surgery, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Li Bai
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Fourth Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Wei Hou
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Shan Tang
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Fourth Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- First Department of Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, China
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Vahedi H, Atefi M, Entezari MH, Hassanzadeh A. The effect of sesame oil consumption compared to sunflower oil on lipid profile, blood pressure, and anthropometric indices in women with non-alcoholic fatty liver disease: a randomized double-blind controlled trial. Trials 2022; 23:551. [PMID: 35804451 PMCID: PMC9264500 DOI: 10.1186/s13063-022-06451-1] [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: 10/29/2021] [Accepted: 06/08/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the world. There is strong evidence that dyslipidemia and other cardio-metabolic disorders are highly prevalent in patients with NAFLD. This trial aimed at examining the effect of sesame oil (SO) in the context of a weight loss program on lipid profile, blood pressure, and anthropometric indices in women with NAFLD. METHODS This randomized, double-blind, controlled trial was carried out on 60 women with NAFLD. Subjects were randomly assigned to the SO group (n = 30) and sunflower oil (SFO) group (n = 30), each person consuming 30 g of oil per day for 12 weeks. All the participants received a hypocaloric diet (- 500 kcal/day) during the study. Lipid profile, blood pressure, and anthropometric indices were assessed at pre- and post-intervention phases. RESULTS In total, 53 participants completed the study. Following 12 weeks of intervention, anthropometric indices (p < 0.001) and systolic blood pressure (SBP) (p < 0.05) were significantly decreased in both groups and diastolic blood pressure (DBP) was significantly decreased in So group (p = 0.03). There was no significant change in lipid profile in both groups (p > 0.05). After adjusting for confounders, DBP (p = 0.031) and total cholesterol (TC) divided by high-density lipoprotein cholesterol (HDL-C) (p = 0.039) in the SO group were significantly reduced compared to the SFO group (p < 0.05). CONCLUSIONS The present clinical trial revealed that SO and SFO may not differently affect anthropometric indices, SBP, and lipid profile except for TC/HDL-C. In addition, SO may be effective in improvement of DBP and TC/HDL-C compared to the SFO group. TRIAL REGISTRATION Ethical approval of this trial was obtained at Isfahan University of Medical Sciences with the reference number of IR.MUI. RESEARCH REC.1399.548 ( https://ethics. RESEARCH ac.ir/ProposalCertificateEn.php?id=158942&Print=true&NoPrintHeader=true&NoPrintFooter=true&NoPrintPageBorder=true&LetterPrint=true ), and it was registered before the start of the patient recruitment on December 12th, 2020 in the Iranian Registry of Clinical Trials (IRCT) with the registration number of IRCT20140208016529N6 .
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Affiliation(s)
- Hamid Vahedi
- Department of Gastroenterology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Islamic Republic of Iran
| | - Masoumeh Atefi
- Department of Clinical Nutrition, School of Nutrition & Food Science, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
| | - Mohammad Hassan Entezari
- Food Security Research Centre and Department of Clinical Nutrition, School of Nutrition & Food Science, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
| | - Akbar Hassanzadeh
- Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
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Doustmohammadian A, Nouri Saeidlou S, Esfandyari S, Gholizadeh E, Maadi M, Motamed N, Ajdarkosh H, Khoonsari M, Clark CCT, Zamani F. Dietary Acid Load (DAL), Glycated Hemoglobin A1c (HbA1c), and Metabolic Syndrome (MeS) Mediate the Association of the Adherence to the Dietary Approaches to Stopping Hypertension (DASH) and Mediterranean Diet (MeD) With Nonalcoholic Fatty Liver Disease. Front Nutr 2022; 9:921415. [PMID: 35873411 PMCID: PMC9301207 DOI: 10.3389/fnut.2022.921415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
The study aimed to investigate the association of adults adhering to Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diet (MeD) with nonalcoholic fatty liver disease (NAFLD) using structural equation modeling (SEM) in Iran. In this population-based cross-sectional study, 3,220 adults (44.65% female) aged ≥18 years were selected from the Amol Cohort Study (AmolCS). The dietary intakes were assessed by a validated 168-item semi-quantitative food-frequency questionnaire (FFQ). Residual method energy adjustment of MeD and DASH scores were calculated. Demographic characteristics and anthropometric and laboratory measurements were collected. NAFLD was diagnosed by an expert radiologist via ultrasound sonography. Based on the primary hypothesis, DASH, MeD, and NAFLD were fitted into models. Metabolic syndrome (MeS) as a potential risk factor directly affected NAFLD risk in all these models. In both genders, the higher adherence to DASH negatively affected NAFLD risk indirectly through the two following paths. (1) Dietary acid load (DAL) and metabolic syndrome (2) DAL and hemoglobin A1c (HbA1c). In addition, the higher DAL positively affected NAFLD risk among male participants indirectly via increasing HbA1c level and MeS (from DAL to HbA1c: β = 0.07, P < 0.001; from HbA1c to MeS: β = 0.10, P < 0.001). Similarly, in both genders, the relationship between MeD and NAFLD was mediated through (1) DAL, HbA1c, and MeS and (2) DAL and MeS. Further, among male participants, the MeD and NAFLD risk were also associated via the mediators of HbA1c and MeS. In female participants, the higher MeD score was directly associated with a reduction of NAFLD risk (β = -0.07, P = 0.008). The present study found three important mediators, including DAL, HbA1c, and MeS, in the association of DASH and MeD scores with NAFLD risk. Preventive and therapeutic interventions should target the mediators, including DAL, HbA1c, MeS, and its components, to reduce NAFLD incidence in the general population.
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Affiliation(s)
- Azam Doustmohammadian
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sakineh Nouri Saeidlou
- Food and Beverages Safety Research Center, Urmia University of Medical Science, Urmia, Iran
| | | | - Esmaeel Gholizadeh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mansooreh Maadi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmoodreza Khoonsari
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Cain C. T. Clark
- Centre for Intelligent Healthcare, Coventry University, Coventry, United Kingdom
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
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Sex hormone binding globulin as a potential drug candidate for liver-related metabolic disorders treatment. Biomed Pharmacother 2022; 153:113261. [PMID: 35738176 DOI: 10.1016/j.biopha.2022.113261] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022] Open
Abstract
Sex hormone binding globulin (SHBG) is a hepatokine that binds to circulating steroid hormones (testosterone, oestradiol) to regulate their concentration in the bloodstream. Recently SHBG was recognized as an essential biomarker for metabolic syndrome (MetS) and hepatic steatosis development. At the hepatic level, the production of SHBG is mainly regulated by sex steroids and thyroxine. Studies of various research groups, including ours, showed that SHBG could be considered a reliable marker of insulin resistance and, therefore, can serve as a predictor of type 2 diabetes. Moreover, increased levels of circulating pro-inflammatory mediators strongly correlate with lowered serum levels of SHBG. This review paper emphasizes the role of SHBG as a potential drug candidate in the course of various metabolic dysfunctions, including non-alcoholic fatty liver disease (NAFLD), obesity, diabetes mellitus and insulin resistance. The studies related to SHBG and its role in the course of metabolic disorders are very limited. Here, we have summarized the most current knowledge about SHBG and its mechanism of action, indicating a novel concept for its possible therapeutic application in the management framework of commonly occurring metabolic dysfunctions.
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Abstract
Introduction: Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.Areas covered: By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.Expert opinion: Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.
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Affiliation(s)
- Carlos Jose Pirola
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (Conicet)-university of Buenos Aires. Institute of Medical Research (IDIM)
| | - Silvia Sookoian
- School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina.,Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires. Institute of Medical Research (IDIM), Buenos Aires, Argentina
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Identification of Key Target Genes and Pathway Analysis in Nonalcoholic Fatty Liver Disease Via Integrated Bioinformatics Analysis. Balkan J Med Genet 2022; 25:25-34. [PMID: 36880036 PMCID: PMC9985361 DOI: 10.2478/bjmg-2022-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Purpose This study aimed at exploring the mechanisms underlying nonalcoholic fatty liver disease (NAFLD) and developing new diagnostic biomarkers for nonalcoholic steatohepatitis (NASH). Methods The microarray dataset GES83452 was downloaded from the NCBI-GEO database, and the differentially expressed RNAs (DERs) were screened between the NAFLD and non-NAFLD samples of the baseline and 1-year follow-up time point group based on the Limma package. Results A total of 561 DERs (268 downregulated and 293 upregulated) were screened in the baseline time point group, and 1163 DERs (522 downregulated and 641 upregulated) were screened in the 1-year follow-up time point group. A total of 74 lncRNA-miRNA pairs and 523 miRNA-mRNA pairs were obtained in order to construct a lncRNA-miRNA-mRNA regulatory network. Subsequently, functional enrichment analysis revealed 28 GO and 9 KEGG pathways in the ceRNA regulatory network. LEPR and CXCL10 are involved in the Cytokine-cytokine receptor interaction (P = 1.86E-02), and the FOXO1 is involved in both the insulin signaling pathway (P = 1.79E-02) and the pathways in cancer (P = 2.87E-02). Conclusion LEPR, CXCL10, and FOXO1 were the characteristic target genes for NAFLD.
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Fan J, Luo S, Ye Y, Ju J, Zhang Z, Liu L, Yang J, Xia M. Prevalence and risk factors of metabolic associated fatty liver disease in the contemporary South China population. Nutr Metab (Lond) 2021; 18:82. [PMID: 34496912 PMCID: PMC8425111 DOI: 10.1186/s12986-021-00611-x] [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] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/25/2021] [Indexed: 02/08/2023] Open
Abstract
Background As a newly proposed diagnosis, data on the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rare. We aimed to assess the prevalence and risk factors of MAFLD using new definition in the contemporary South China population. Methods In this population based, cross sectional study, a total of 5377 participants aged 30–79 years old were recruited from the South China between 2018 and 2019. MAFLD was diagnosed in subjects who have both hepatic steatosis and metabolic disorders according to the newly international expert consensus. The total prevalence of MAFLD and prevalence by sex and age was estimated. Demographic characteristics, history of disease, and lifestyle were recorded by participants on a questionnaire. Abdominal ultrasonography was performed and evaluated by experienced sonographers. Multivariable logistic regression was used to calculate the odds ratios (ORs) of MAFLD. Results Overall prevalence of MAFLD was 29.2% (95% confidence interval [CI] 28.0% to 30.5%). Prevalence was higher in women (31.7%) than in men (25.5%; p < 0.001 for sex difference) and in subjects aged 50 years or older (30.7%) than in those aged 30–49 years (19.8%; p < 0.001 for age difference). In participants diagnosed with MAFLD, the prevalence of overweight/obesity was up to 90.5%, type 2 diabetes (T2DM) and metabolic dysregulation were 25.0% and 62.2%, respectively. Risk factors for MAFLD included overweight/obesity (OR = 4.67; 95% CI, 3.76–5.83), T2DM (OR = 2.41, 95% CI, 1.68–3.47), hypertriglyceridemia (OR = 2.42, 95% CI, 2.03–2.87), high school education (OR = 1.50, 95% CI, 1.23–1.82), high income (OR = 1.22, 95% CI, 1.05–1.42). A lower risk of MAFLD was associated with high physical activity equivalent (OR = 0.71, 95% CI, 0.60–0.85). A U-shaped association of frequency of soups and ORs of MAFLD was found, the adjusted ORs (95% CI) of lower and higher frequency of soups were 1.58 (1.32–1.89) and 1.36 (1.13–1.63), respectively. Conclusions Our results showed a high prevalence of MAFLD in the general adult population in South China. Obesity has the greatest impact on MAFLD, physical activity and moderate consumption of soups might be the potential protective factors of MAFLD. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00611-x.
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Affiliation(s)
- Jiahua Fan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Shiyun Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Yongxin Ye
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Jingmeng Ju
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Zhuoyu Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Ludi Liu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Jialu Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Min Xia
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China.
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Pirola CJ, Sookoian S. The lipidome in nonalcoholic fatty liver disease: actionable targets. J Lipid Res 2021; 62:100073. [PMID: 33845089 PMCID: PMC8121699 DOI: 10.1016/j.jlr.2021.100073] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Recent technological advances, combined with OMICs experiments and explorations involving different biological samples, have uncovered vital aspects of NAFLD biology. In this review, we summarize recent work by our group and others that expands what is known about the role of lipidome in NAFLD pathogenesis. We discuss how pathway and enrichment analyses were performed by integrating a list of query metabolites derived from text-mining existing NAFLD-lipidomics studies, resulting in the identification of nine Kyoto Encyclopedia of Genes and Genomes dysregulated pathways, including biosynthesis of unsaturated fatty acids, butanoate metabolism, synthesis and degradation of ketone bodies, sphingolipid, arachidonic acid and pyruvate metabolism, and numerous nonsteroidal antiinflammatory drug pathways predicted from The Small Molecule Pathway Database. We also summarize an integrated pathway-level analysis of genes and lipid-related metabolites associated with NAFLD, which shows overrepresentation of signal transduction, selenium micronutrient network, Class A/1Rhodopsin-like receptors and G protein-coupled receptor ligand binding, and G protein-coupled receptor downstream signaling. Generated gene-metabolite-disease interaction networks indicate that NAFLD and arterial hypertension are interlinked by molecular signatures. Finally, we discuss how mining pathways and associations among metabolites, lipids, genes, and proteins can be exploited to infer networks and potential pharmacological targets and how lipidomic studies may provide insight into the interrelationships among metabolite clusters that modify NAFLD biology, genetic susceptibility, diet, and the gut microbiome.
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Affiliation(s)
- Carlos J Pirola
- Instituto de Investigaciones Médicas A Lanari, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Departamento de Genética y Biología Molecular de Enfermedades Complejas, Instituto of Investigaciones Médicas (IDIM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
| | - Silvia Sookoian
- Instituto de Investigaciones Médicas A Lanari, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Departamento de Hepatología Clínica y Molecular, Instituto of Investigaciones Médicas (IDIM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
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Michalak A, Cichoż-Lach H, Guz M, Kozicka J, Cybulski M, Jeleniewicz W. Plateletcrit and Mean Platelet Volume in the Evaluation of Alcoholic Liver Cirrhosis and Nonalcoholic Fatty Liver Disease Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8867985. [PMID: 33644233 PMCID: PMC7901043 DOI: 10.1155/2021/8867985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/07/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
Platelet (PLT) indices have been proposed as potential markers in the assessment of liver fibrosis and exacerbation of liver failure. The aim of our study was to verify mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) in alcohol-related liver cirrhosis (ALC) and nonalcoholic fatty liver disease (NAFLD) patients. One hundred forty-two patients with ALC, 92 with NAFLD, and 68 in control group were enrolled in this study. Hematological indices (MPV, PCT, and PDW) and serological (indirect and direct) markers of liver fibrosis (AAR, APRI, FIB-4, GPR, PICP, PIIINP, TGF-α, PDGF-AB, laminin) were measured in each participant. MELD score in ALC patients and NAFLD fibrosis score (NFS) together with BARD score in the NAFLD group were also obtained. Results were compared between research and control groups. Then, a correlation between evaluated indices was performed in study groups. Receiver operating characteristic curves (ROCs) and area under the curve (AUC) values were applied to assess the diagnostic accuracy of measured indices. Significant increase in PDW and decrease in PCT in comparison to controls were noted in examined ALC (60.4% vs. 51.2% and 0.1% vs. 0.21%, respectively, p < 0.0001) and NAFLD (54.75% vs. 51.2% and 0.19 vs. 0.21%, respectively, p < 0.01) patients. Decreased level of MPV was observed in NAFLD group (7.85 fl vs. 8.90 fl, p < 0.0001). Additionally, PCT correlated with NFS (p < 0.0001). Evaluated PLT indices correlated with MELD score (MPV and PDW, p < 0.001; PCT, p < 0.05). They correlated with indirect and direct markers of liver fibrosis in the whole research group, too. PCT was the parameter with the greatest diagnostic accuracy in ALC patients (AUC = 0,839 for cutoff < 0.17%); in NAFLD group, it was MPV (AUC = 0,808 for cutoff < 7.9 fl). PCT in ALC and MPV in NAFLD can be perceived as potential diagnostic markers.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Małgorzata Guz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Joanna Kozicka
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Marek Cybulski
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Witold Jeleniewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
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Pirola CJ, Sookoian S. NAFLD and Cardiometabolic Risk Factors: The Liver Fibrosis Trajectory Through the Lens of Biological Interactions. Hepatology 2021; 73:479-482. [PMID: 33280151 DOI: 10.1002/hep.31672] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Carlos J Pirola
- Facultad de Medicina, Instituto de Investigaciones Médicas A LanariUniversidad de Buenos AiresCiudad Autónoma de Buenos AiresArgentina.,Departamento of Genética y Biología Molecular de Enfermedades ComplejasConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Instituto of Investigaciones Médicas (IDIM)Ciudad Autónoma de Buenos AiresArgentina
| | - Silvia Sookoian
- Facultad de Medicina, Instituto de Investigaciones Médicas A LanariUniversidad de Buenos AiresCiudad Autónoma de Buenos AiresArgentina.,Departamento de Hepatología Clínica y MolecularConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Instituto of Investigaciones Médicas (IDIM)Ciudad Autónoma de Buenos AiresArgentina
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Pirola CJ, Salatino A, Sookoian S. Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system. World J Gastroenterol 2021; 27:305-320. [PMID: 33584064 PMCID: PMC7852588 DOI: 10.3748/wjg.v27.i4.305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/19/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.
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Affiliation(s)
- Carlos Jose Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Adrian Salatino
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Silvia Sookoian
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
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Ismaiel A, Dumitrascu DL. Genetic predisposition in metabolic-dysfunction-associated fatty liver disease and cardiovascular outcomes-Systematic review. Eur J Clin Invest 2020; 50:e13331. [PMID: 32589269 DOI: 10.1111/eci.13331] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Despite the demonstrated increased cardiovascular (CV) risk associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), genetic variants predisposing to MAFLD were not constantly associated with CV events. Recently, rs641738C > T near membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) has been studied in MAFLD and CV outcomes. Therefore, we aimed to evaluate the association between rs641738C > T in the presence and severity of hepatic steatosis, fibrosis, biochemical markers and progression to hepatocellular carcinoma (HCC), in addition to CV outcomes in MAFLD. MATERIALS AND METHODS An electronic search on PubMed, Embase and Cochrane Library for articles published till 23 March 2020 was systematically performed. Articles were screened, and data extracted from eligible studies by two reviewers independently. RESULTS Studies conducted on adults with MAFLD involving European, Hispanic and African American populations evaluating rs641738 reported reduced hepatic expression of MBOAT7, increased hepatic fat content, severity of MAFLD, susceptibility to develop NASH, advanced fibrosis and HCC in adults. However, most articles involving Asian individuals contradicted these findings. Studies involving obese children associated rs641738 with increased plasma alanine aminotransferase (ALT) levels, while its association with MAFLD remains inconsistent. The rs641738 variant was assessed as a MAFLD susceptibility gene in coronary artery disease (CAD) reporting neutral effects. CONCLUSIONS Despite inconclusive results in Asian populations, rs641738C > T near MBOAT7 is associated with increased hepatic fat, MAFLD severity, susceptibility to develop NASH, advanced fibrosis and HCC in adults from Caucasian, Hispanic and African American ethnicities with MAFLD, as well as elevated ALT levels in children, while exerting neutral effects in CAD.
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Affiliation(s)
- Abdulrahman Ismaiel
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, Cluj-Napoca, Romania
| | - Dan L Dumitrascu
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, Cluj-Napoca, Romania
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35
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BMI, high-sensitivity C-reactive protein and the conversion from metabolically healthy to unhealthy phenotype in Chinese adults: a cohort study. Public Health Nutr 2020; 24:4124-4131. [PMID: 32840191 DOI: 10.1017/s136898002000289x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE We performed the cohort study to evaluate the association between BMI, high-sensitivity C-reactive protein (hs-CRP) and the conversion from metabolically healthy to unhealthy phenotype in Chinese adults. DESIGN Metabolically healthy was defined as participants without history of metabolic diseases and with normal fasting blood glucose level, glycated Hb A1c level, blood pressure, lipid profile, serum uric acid level and liver ultrasonographic findings at baseline. Participants were either classified into normal weight (18·5 ≤ BMI < 24·0 kg/m2) and overweight (BMI ≥ 24·0 kg/m2) based on baseline BMI, or low (<1 mg/l) and high (≥1 mg/l) groups based on baseline hs-CRP. The conversion from metabolically healthy to unhealthy phenotype was deemed if any of the metabolic abnormalities had been confirmed twice or more during 5 years of follow-up. RESULTS Included were 4855 (1942 men and 2913 women, aged 36·0 ± 8·9 years) metabolically healthy Chinese adults. We identified 1692 participants who converted to metabolically unhealthy phenotype during the follow-up. Compared with their counterparts, the adjusted hazards ratio of the conversion was 1·19 (95 % CI 1·07, 1·33) for participants with overweight, while it was 1·15 (95 % CI 1·03, 1·29) for those with high hs-CRP level (≥1 mg/l). Further adjustment of hs-CRP did not materially change the association between BMI and the conversion. However, the association between hs-CRP and the conversion was not significant after further adjustment of BMI. The sensitivity analysis generated similar results to main analysis. CONCLUSION BMI was associated with the risk of the conversion from metabolically healthy to unhealthy status in Chinese adults.
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Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clin Mol Hepatol 2020; 26:430-443. [PMID: 32791578 PMCID: PMC7641556 DOI: 10.3350/cmh.2020.0137] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti-diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first-line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD.
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Affiliation(s)
- Kyung-Soo Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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37
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Sookoian S, Salatino A, Castaño GO, Landa MS, Fijalkowky C, Garaycoechea M, Pirola CJ. Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease. Gut 2020; 69:1483-1491. [PMID: 31900291 DOI: 10.1136/gutjnl-2019-318811] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE We aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features-from moderate to severe obesity-may be associated with significant changes in the microbial DNA profile. DESIGN AND METHODS Liver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing. RESULTS Liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)-specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)-were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences. CONCLUSION This is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×104 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.
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Affiliation(s)
- Silvia Sookoian
- Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina .,Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council, Buenos Aires, Argentina
| | - Adrian Salatino
- Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina.,Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council, Buenos Aires, Argentina
| | - Gustavo Osvaldo Castaño
- Liver Unit, Medicine and Surgery Department, Hospital General de Agudos Dr Abel Zubizarreta, Buenos Aires, Argentina
| | - Maria Silvia Landa
- Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina.,Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council, Buenos Aires, Argentina
| | - Cinthia Fijalkowky
- Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina.,Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council, Buenos Aires, Argentina
| | | | - Carlos Jose Pirola
- Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina .,Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council, Buenos Aires, Argentina
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38
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Meroni M, Longo M, Fracanzani AL, Dongiovanni P. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD. EBioMedicine 2020; 57:102866. [PMID: 32629394 PMCID: PMC7339032 DOI: 10.1016/j.ebiom.2020.102866] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/11/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Anna L Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy.
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Zhang M, Lin S, Wang MF, Huang JF, Liu SY, Wu SM, Zhang HY, Wu ZM, Liu WY, Zhang DC, Hao CM, Zhu YY, Zheng MH, Wang XZ. Association between NAFLD and risk of prevalent chronic kidney disease: why there is a difference between east and west? BMC Gastroenterol 2020; 20:139. [PMID: 32375660 PMCID: PMC7203801 DOI: 10.1186/s12876-020-01278-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUNDS There is a discrepancy between west and east on the relationship between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). This study aimed to find out the possible reason for this and to clarify the association between NAFLD and CKD by analyzing two population-based datasets from the US and China. METHODS Two health examination datasets from China and the US were used. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 or and/or abnormal albuminuria and/or overt proteinuria. Binary logistic regression was used to examine the association between NAFLD and CKD. RESULTS A total of 60,965 participants were analyzed, including 11,844 from the US and 51,229 from China. The prevalence of NAFLD was 27.12% in the Chinese population and 36.08% in the US population (p < 0.001). The proportions of CKD and late stage CKD (stages 3-5) were higher in the US population than the Chinese one. NAFLD was independently associated with an increased risk of CKD in Chinese population, whereas in the US population, the NAFLD was not an independent risk factor of CKD. In subgroup analyses which excluded late stages CKD (stages 3-5), the risks of mild renal function decline became consistent: NAFLD was associated with early stages of CKD but not the late stages of CKD in both populations. CONCLUSION NAFLD increased the risk of early stages of CKD in both Chinese and the US population. The conflicting results reported by previous studies might result from the different proportion of late stages of CKD.
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Affiliation(s)
- Min Zhang
- Division of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China
| | - Su Lin
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Ming-Fang Wang
- Liver Research Center, the First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian, China
| | - Jiao-Feng Huang
- Liver Research Center, the First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian, China
| | - Shi-Ying Liu
- Liver Research Center, the First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian, China
| | - Su-Mei Wu
- Liver Research Center, the First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian, China
| | - Hao-Yang Zhang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China
| | - Zi-Mu Wu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Wen-Yue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dong-Chu Zhang
- Wenzhou Medical Center, Wenzhou People's Hospital, Wenzhou, China
| | - Chuan-Ming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, China
| | - Yue-Yong Zhu
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
| | - Xiao-Zhong Wang
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, China.
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40
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Lonardo A, Baldelli E. Methodological Tools for Exploring Novel Biopharmaceutical Approaches to the Metabolic Syndrome and Related Disorders : A Commentary on: Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease. A Focus on Early Phase Clinical Drug Development, Second Edition. Diabetes Ther 2020; 11:773-777. [PMID: 32146692 PMCID: PMC7136372 DOI: 10.1007/s13300-020-00794-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Indexed: 02/07/2023] Open
Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
| | - Enrica Baldelli
- Università degli Studi di Modena e Reggio Emilia, Modena, Italy
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Ma Z, Xu C, Kang X, Zhang S, Li H, Tao L, Zheng D, Guo X, Yang X. Changing trajectories of serum uric acid and risk of non-alcoholic fatty liver disease: a prospective cohort study. J Transl Med 2020; 18:133. [PMID: 32192511 PMCID: PMC7081554 DOI: 10.1186/s12967-020-02296-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND It is unclear the role of longitudinal trajectory of serum uric acid (SUA) on the development of non-alcoholic fatty liver disease (NAFLD). We aimed to determine whether longitudinal SUA trajectories are associated with the risk of new-onset NAFLD. METHODS We explored the relationship between SUA trajectories and NAFLD in a cohort including 3822 participants. Individual's SUA trajectories from 2012 to 2014 were defined using group-based trajectory modeling analysis in four distinct patterns: trajectory 1 (n = 991, 25.93%), trajectory 2 (n = 1421, 37.18%), trajectory 3 (n = 1156, 30.22%), and trajectory 4 (n = 254, 6.67%). The logistic regression model was used to evaluate the association between SUA changing trajectories and subsequent NAFLD until 2016. Dose-response relationship between SUA changing trajectories and NAFLD risk was evaluated through the testing of trajectory groups as a continuous variable. RESULTS The 2-year incidence of NAFLD was 13.27%. Compared with trajectory 1, the adjusted odds risk for NAFLD development was in a dose-response relationship as follows: 1.27 (95% CI 0.91-1.78) for trajectory 2, 1.89 (95% CI 1.29-2.75) for trajectory 3, and 2.34 (95% CI 1.43-3.83) for trajectory 4. And this dose-response relationship was not affected by age, sex, and abdominal obesity. CONCLUSIONS Higher SUA changing trajectory is a risk factor for NAFLD. This finding highlights the importance of paying attention to SUA changing trajectory on the detection and prevention of NAFLD.
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Affiliation(s)
- Zhimin Ma
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Chaonan Xu
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Medical Engineering Department, Peking University Third Hospital, NO. 49 HuaYuan BeiLu, Haidian District, Beijing, 100191, China
| | - Xiaoping Kang
- Beijing Xiaotangshan Hospital, NO. 390 Wenquan Street, Xiaotangshan Town, Changping District, Beijing, 102211, China
| | - Shan Zhang
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Haibin Li
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Lixin Tao
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Deqiang Zheng
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Xiuhua Guo
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China
| | - Xinghua Yang
- School of Public Health, Capital Medical University, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China.
- Beijing Municipal Key Laboratory of Clinical Epidemiology, NO. 10 Xitoutiao, Youanmen, Fengtai District, Beijing, 100069, China.
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Xu R, Gao X, Wan Y, Fan Z. Association of Metabolically Healthy Overweight Phenotype With Abnormalities of Glucose Levels and Blood Pressure Among Chinese Adults. JAMA Netw Open 2019; 2:e1914025. [PMID: 31651967 PMCID: PMC6822082 DOI: 10.1001/jamanetworkopen.2019.14025] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
IMPORTANCE Whether the metabolically healthy overweight (MHO) phenotype is resistant to metabolic abnormalities remains unknown. OBJECTIVE To evaluate the association of MHO with glucose level abnormalities and high blood pressure (BP) in Chinese adults. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted from January 1, 2013, to October 31, 2018, in the Health Management Center at Ren Ji Hospital, Shanghai, China, using data from 55 155 recruited Chinese adults. Body weight, fasting blood glucose (FBG) level, hemoglobin A1c (HbA1c) level, and BP were measured annually. EXPOSURES Metabolically healthy overweight was defined as a body mass index (calculated as weight in kilograms divided by height in meters squared) of 24.0 in 2013 (baseline) and 2014, no history of metabolic diseases, and normal FBG level, HbA1c level, BP, lipid profile, serum uric acid level, and liver ultrasonographic findings at baseline; the remaining participants were defined as being metabolically healthy normal. MAIN OUTCOMES AND MEASURES Glucose level abnormality was confirmed if the FBG level was 101 mg/dL or greater or the HbA1c level was 5.7%, and high BP was confirmed if the systolic BP was 130 mm Hg or higher or the diastolic BP was 80 mm Hg or higher at least twice during the subsequent 4 years of follow-up. RESULTS A total of 3204 metabolically healthy Chinese adults (mean [SD] age, 39.8 [10.9] years; 1940 women [60.5%]) were included in the study. The prevalence of MHO was 7.0%. A total of 146 incident cases of glucose level abnormality and 220 cases of high BP during 4 years of follow-up were identified. Compared with the metabolically healthy normal group, the MHO group had a higher risk of glucose level abnormality (adjusted hazard ratio, 2.36; 95% CI, 1.52-3.64) and high BP (adjusted hazard ratio, 1.73; 95% CI, 1.18-2.53) after adjusting for several potential confounders. CONCLUSIONS AND RELEVANCE Metabolically healthy overweight may be associated with a high future risk of glucose abnormality and high BP in Chinese adults. If the individuals are confirmed with MHO, early interventions, including diet and exercise, should be recommended to decrease the risk of developing abnormalities of glucose and BP.
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Affiliation(s)
- Renying Xu
- Ren Ji Hospital, School of Medicine, Department of Clinical Nutrition, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang Gao
- Department of Nutritional Sciences, The Pennsylvania State University, University Park
| | - Yanping Wan
- Ren Ji Hospital, School of Medicine, Department of Clinical Nutrition, Shanghai Jiao Tong University, Shanghai, China
| | - Zhuping Fan
- Ren Ji Hospital, School of Medicine, Department of Digestion, Shanghai Jiao Tong University, Shanghai, China
- Ren Ji Hospital, School of Medicine, Department of Health Management, Shanghai Jiao Tong University, Shanghai, China
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Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K. Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care 2019; 42:1481-1488. [PMID: 31332029 DOI: 10.2337/dc19-0167] [Citation(s) in RCA: 226] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH. RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters. RESULTS More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group. CONCLUSIONS In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Diane M Biernacki
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Sreevidya K Subbarayan
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Jinping Lai
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Fermin Tio
- Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Amitabh Suman
- Division of Gastroenterology, Hepatology, and Nutrition, Malcom Randall VA Medical Center, Gainesville, FL
| | - Beverly K Orsak
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Joan Hecht
- Division of Diabetes, Audie L. Murphy Memorial VA Hospital, San Antonio, TX
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
- Division of Endocrinology, Diabetes and Metabolism, Malcom Randall VA Medical Center, Gainesville, FL
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Sookoian S, Pirola CJ. Repurposing drugs to target nonalcoholic steatohepatitis. World J Gastroenterol 2019; 25:1783-1796. [PMID: 31057294 PMCID: PMC6478618 DOI: 10.3748/wjg.v25.i15.1783] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/21/2019] [Accepted: 03/30/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires 1427, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autonoma de Buenos Aires 1427, Argentina
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D'Adamo E, Castorani V, Nobili V. The Liver in Children With Metabolic Syndrome. Front Endocrinol (Lausanne) 2019; 10:514. [PMID: 31428049 PMCID: PMC6687849 DOI: 10.3389/fendo.2019.00514] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as an emerging health risk in obese children and adolescents. NAFLD represents a wide spectrum of liver conditions, ranging from asymptomatic steatosis to steatohepatitis. The growing prevalence of fatty liver disease in children is associated with an increased risk of metabolic and cardiovascular complications. NAFLD is considered the hepatic manifestation of Metabolic Syndrome (MetS) and several lines of evidence have reported that children with NAFLD present one or more features of MetS. The pathogenetic mechanisms explaining the interrelationships between fatty liver disease and MetS are not clearly understood. Altough central obesity and insulin resistance seem to represent the core of the pathophysiology in both diseases, genetic susceptibility and enviromental triggers are emerging as crucial components promoting the development of NAFLD and MetS in children. In the present review we have identified and summarizied studies discussing current pathogenetic data of the association between NAFLD and MetS in children.
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Affiliation(s)
- Ebe D'Adamo
- Department of Neonatology, University of Chieti, Chieti, Italy
- *Correspondence: Ebe D'Adamo
| | | | - Valerio Nobili
- Department of Pediatrics, University “La Sapienza”, Rome, Italy
- Hepatology, Gastroenterology and Nutrition Unit, IRCCS “Bambino Gesù” Children's Hospital, Rome, Italy
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