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Li R, Su K, Wu T, Xu L, Song W, Sun D, Zeng T, Chen J, Xin H, Li Y, Zang M, Hu M. Genome-wide enhancer-gene regulatory maps of liver reveal novel regulatory mechanisms underlying NAFLD pathogenesis. BMC Genomics 2025; 26:493. [PMID: 40375105 PMCID: PMC12082939 DOI: 10.1186/s12864-025-11668-w] [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: 01/04/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation. RESULTS In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels. CONCLUSIONS Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.
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Affiliation(s)
- Ruofan Li
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Kaiyan Su
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China
| | - Tianzhun Wu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Li Xu
- Department of Hepatopancreatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Wenyu Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Dandan Sun
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Tao Zeng
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Haibei Xin
- Department of Hepatobiliary Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
| | - Yuanfeng Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
| | - Mengya Zang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Minggen Hu
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China.
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China.
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Ramirez CB, Ahn IS, Rubtsova VI, Cely I, Le J, Kim J, Jung S, Kelly ME, Kim Y, Bae H, Song WS, Alam YH, Zhang G, Diamante G, Chao A, Hoffner L, Anica A, Le I, Lopez ML, Tamburini IJ, Moyer EM, Tsai A, Yang Q, Dai X, Piomelli D, Lee G, Yang X, Jang C. Circulating glycerate predicts resilience to fructose-induced hepatic steatosis. Cell Metab 2025; 37:1223-1234.e5. [PMID: 40267913 PMCID: PMC12058382 DOI: 10.1016/j.cmet.2025.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 11/18/2024] [Accepted: 03/28/2025] [Indexed: 04/25/2025]
Abstract
Excessive intake of dietary fructose increases the risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and cancers. However, what host factors determine disease vulnerability is incompletely understood. Here, we leverage genetically divergent mouse strains, mass spectrometry-based metabolomics, and in vivo isotope tracing, identifying circulating glycerate as a biomarker that predicts resilience to fructose-induced hepatic steatosis in both sexes. We found that the surge of circulating glycerate after an oral fructose provision reflects strong small-intestinal fructose catabolism. Such fructose clearance by the small intestine is linked to a weaker induction of hepatic de novo lipogenesis and steatosis upon chronic fructose exposure across strains. These data indicate the potential utility of an oral fructose tolerance test and circulating glycerate measurements to predict an individual's susceptibility to fructose-elicited steatotic liver and provide personalized dietary recommendations.
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Affiliation(s)
- Cuauhtemoc B Ramirez
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - In Sook Ahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Varvara I Rubtsova
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - Ingrid Cely
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Johnny Le
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Joohwan Kim
- Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - Sunhee Jung
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Miranda E Kelly
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Yeojin Kim
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Hosung Bae
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Won-Suk Song
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Yasmine H Alam
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Guanglin Zhang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alina Chao
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Lauren Hoffner
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - Alexis Anica
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - Izabelle Le
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA
| | - Miranda L Lopez
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Ian J Tamburini
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Elena M Moyer
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Ariel Tsai
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Qin Yang
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Xing Dai
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Daniele Piomelli
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Gina Lee
- Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA.
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA; Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA, USA.
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Iakovleva V, de Jong YP. Gene-based therapies for steatotic liver disease. Mol Ther 2025:S1525-0016(25)00298-9. [PMID: 40254880 DOI: 10.1016/j.ymthe.2025.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/26/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025] Open
Abstract
Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.
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Affiliation(s)
- Viktoriia Iakovleva
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ype P de Jong
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, USA.
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Yang Y, Chen X, Zhang H, Yang G, Zhu X, Si X, Chen F, Zhao Y, Jin F, Lu J. The correlation between the polymorphism of lysolecithin acyltransferase (MBOAT7) rs641738 and liver fibrosis. Per Med 2025; 22:113-119. [PMID: 40055064 DOI: 10.1080/17410541.2025.2476379] [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: 07/25/2024] [Accepted: 03/04/2025] [Indexed: 03/26/2025]
Abstract
OBJECTIVE We aimed to explore the relationship between the MBOAT7 rs641738 gene polymorphism and liver fibrosis and inflammation. METHODS A total of 214 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were allocated into the mild-to-moderate and severe liver fibrosis groups based on liver fibrosis degree. The genotypes at the MBOAT7 rs641738 locus were evaluated. Differences in clinical and biochemical indicators, as well as the genotype and allele frequency distributions of the MBOAT7 rs641738 polymorphism, were analyzed across groups with varying degrees of liver fibrosis. Additionally, the clinical and biochemical differences among patients with different genotypes were examined. RESULTS Significant differences were observed in the distribution of CC, CT, and TT genotypes, as well as C and T allele frequencies at the MBOAT7 rs641738 locus, between patients with mild-to-moderate and severe fibrosis. Carriers of the CT + TT genotype had a higher risk of developing severe liver fibrosis compared to those with the CC genotype (OR > 1). Furthermore, CT + TT carriers had higher levels of inflammatory cytokines and more severe fibrosis than CC genotype carriers (all p < 0.05). CONCLUSION The MBOAT7 rs641738 gene polymorphism is associated with the severity of liver fibrosis and inflammation.
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Affiliation(s)
- Yuxia Yang
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Xiang Chen
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Huiqin Zhang
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Gang Yang
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Xiaoyun Zhu
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Xiujing Si
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Feilong Chen
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Yan Zhao
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Feng Jin
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Juanjuan Lu
- Department of Digestive, Gansu Provincial Hospital, Lanzhou, Gansu, China
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5
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Huang DQ, Wong VWS, Rinella ME, Boursier J, Lazarus JV, Yki-Järvinen H, Loomba R. Metabolic dysfunction-associated steatotic liver disease in adults. Nat Rev Dis Primers 2025; 11:14. [PMID: 40050362 DOI: 10.1038/s41572-025-00599-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/09/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.
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Affiliation(s)
- Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Vincent W S Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Mary E Rinella
- University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Jerome Boursier
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France
- Laboratoire HIFIH, SFR ICAT 4208, Université d'Angers, Angers, France
| | - Jeffrey V Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- City University of New York Graduate School of Public Health and Health Policy, New York, NY, USA
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, USA.
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA.
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Moore MP, Wang X, Kennelly JP, Shi H, Ishino Y, Kano K, Aoki J, Cherubini A, Ronzoni L, Guo X, Chalasani NP, Khalid S, Saleheen D, Mitsche MA, Rotter JI, Yates KP, Valenti L, Kono N, Tontonoz P, Tabas I. Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation. Hepatology 2025; 81:576-590. [PMID: 38776184 PMCID: PMC11822724 DOI: 10.1097/hep.0000000000000933] [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: 12/19/2023] [Accepted: 04/03/2024] [Indexed: 05/24/2024]
Abstract
BACKGROUND AND AIMS The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. CONCLUSIONS This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.
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Affiliation(s)
- Mary P Moore
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - John Paul Kennelly
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Hongxue Shi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Yuki Ishino
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Alessandro Cherubini
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Luisa Ronzoni
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shareef Khalid
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan
| | - Danish Saleheen
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan
| | - Matthew A Mitsche
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Katherine P Yates
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Luca Valenti
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Nozomu Kono
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Ira Tabas
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York, USA
- Columbia University Digestive and Liver Disease Research Center, New York, NY
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Pei Y, Goh GBB. Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease. Gut Liver 2025; 19:8-18. [PMID: 39774124 PMCID: PMC11736312 DOI: 10.5009/gnl240407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.
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Affiliation(s)
- Yiying Pei
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
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8
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Galvanin C, Buch S, Nahon P, Trépo E. PNPLA3 in Alcohol-Related Liver Disease. Liver Int 2025; 45:e16211. [PMID: 39679853 DOI: 10.1111/liv.16211] [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: 11/18/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024]
Abstract
The discovery of PNPLA3 as a genetic risk factor for liver disease has transformed our understanding of the pathogenesis of alcohol-related liver disease (ALD). The recent reclassification of fatty liver disease as steatotic liver disease (SLD), introducing metabolic dysfunction and alcohol-related liver disease (MetALD), has highlighted how genetic and environmental factors synergistically drive liver damage. The PNPLA3 rs738409 variant stands as a paradigmatic example of gene-environment interaction, where its effect on liver disease is dramatically amplified by alcohol consumption, obesity and type 2 diabetes. Understanding these interactions has revealed novel pathogenic mechanisms. The robust genetic evidence and a growing understanding of molecular mechanisms have made PNPLA3 an attractive therapeutic target. Several compounds targeting PNPLA3 are now in clinical development. While initial trials have focused on metabolic dysfunction-associated SLD, the recognition that almost all individuals with excessive alcohol consumption have metabolic comorbidities provides an unprecedented opportunity to evaluate these genetically informed therapies in MetALD. In this review, we examine the role of PNPLA3 in ALD, focusing on gene-environment interactions and therapeutic implications in the context of the new disease classification framework.
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Affiliation(s)
- Clélia Galvanin
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Stephan Buch
- Department of Medicine I, Dresden University Hospital, Dresden, Germany
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Pierre Nahon
- Service d'Hépatologie, AP-HP Avicenne, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team «Functional Genomics of Solid Tumors», Paris, France
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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9
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Zhang X, Chang KM, Yu J, Loomba R. Unraveling Mechanisms of Genetic Risks in Metabolic Dysfunction-Associated Steatotic Liver Diseases: A Pathway to Precision Medicine. ANNUAL REVIEW OF PATHOLOGY 2025; 20:375-403. [PMID: 39854186 DOI: 10.1146/annurev-pathmechdis-111523-023430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem, affecting ∼1 billion people. This condition is well established to have a heritable component with strong familial clustering. With the extraordinary breakthroughs in genetic research techniques coupled with their application to large-scale biobanks, the field of genetics in MASLD has expanded rapidly. In this review, we summarize evidence regarding genetic predisposition to MASLD drawn from family and twin studies. Significantly, we delve into detailed genetic variations associated with diverse pathogenic mechanisms driving MASLD. We highlight the interplay between these genetic variants and their connections with metabolic factors, the gut microbiome, and metabolites, which collectively influence MASLD progression. These discoveries are paving the way for precise medicine, including noninvasive diagnostics and therapies. The promising landscape of novel genetically informed drug targets such as RNA interference is explored. Many of these therapies are currently under clinical validation, raising hopes for more effective MASLD treatment.
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Affiliation(s)
- Xiang Zhang
- MASLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, California, USA;
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kyong-Mi Chang
- Corporal Michael J. Crescenz VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, California, USA;
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, California, USA
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10
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Chen VL, Brady GF. Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application. Hepatol Commun 2025; 9:e0618. [PMID: 39774697 PMCID: PMC11717516 DOI: 10.1097/hc9.0000000000000618] [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: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.
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Marigorta UM, Millet O, Lu SC, Mato JM. Dysfunctional VLDL metabolism in MASLD. NPJ METABOLIC HEALTH AND DISEASE 2024; 2:16. [PMID: 39049993 PMCID: PMC11263124 DOI: 10.1038/s44324-024-00018-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 06/22/2024] [Indexed: 07/27/2024]
Abstract
Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), linked to factors such as obesity and diabetes, stems from a compromise in the structural and functional stability of the liver within the complexities of lipid metabolism. This compromise inaccurately senses an increase in energy status, such as during fasting-feeding cycles or an upsurge in lipogenesis. Serum lipidomic studies have delineated three distinct metabolic phenotypes, or "metabotypes" in MASLD. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and triglyceride (TG) levels, associated with a reduced risk of cardiovascular disease (CVD). In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with elevated CVD risk. An intermediate subtype, with a blend of features, is designated as the MASLD-B metabotype. In this perspective, we examine into recent findings that show the multifaceted regulation of VLDL secretion by S-adenosylmethionine, the primary cellular methyl donor. Furthermore, we explore the differential CVD and hepatic cancer risk across MASLD metabotypes and discuss the context and potential paths forward to gear the findings from genetic studies towards a better understanding of the observed heterogeneity in MASLD.
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Affiliation(s)
- Urko M. Marigorta
- Integrative Genomics Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
| | - Oscar Millet
- Precision Medicine and Metabolism Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, 48160 Derio, Spain
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA
| | - José M. Mato
- Precision Medicine and Metabolism Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, 48160 Derio, Spain
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12
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Tan S, Li Q, Guo C, Chen S, Kamal-Eldin A, Chen G. Reveal the mechanism of hepatic oxidative stress in mice induced by photo-oxidation milk using multi-omics analysis techniques. J Adv Res 2024:S2090-1232(24)00271-6. [PMID: 38986809 DOI: 10.1016/j.jare.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/06/2024] [Accepted: 07/06/2024] [Indexed: 07/12/2024] Open
Abstract
INTRODUCTION Photo-oxidation is recognized as a contributor to the deterioration of milk quality, posing potential safety hazards to human health. However, there has been limited investigation into the impact of consuming photo-oxidized milk on health. OBJECTIVES This study employs multi-omics analysis techniques to elucidate the mechanisms by which photo-oxidized milk induces oxidative stress in the liver. METHODS Mouse model was used to determine the effect of the gavage administration of milk with varying degrees of photo-oxidation on the mouse liver. The damage degree was established by measuring serum markers indicative of oxidative stress, and with a subsequent histopathological examination of liver tissues. In addition, comprehensive metabolome, lipidome, and transcriptome analyses were conducted to elucidate the underlying molecular mechanisms of hepatic damage caused by photo-oxidized milk. RESULTS A significant elevation in the oxidative stress levels and the presence of hepatocellular swelling and inflammation subsequent to the gavage administration of photo-oxidized milk to mice. Significant alterations in the levels of metabolites such as lumichrome, all-trans-retinal, L-valine, phosphatidylglycerol, and phosphatidylcholine within the hepatic tissue of mice. Moreover, photo-oxidized milk exerted a pronounced detrimental impact on the glycerophospholipid metabolism of mice liver. The peroxisome proliferator-activated receptors (PPAR) signaling pathway enrichment appreciated in the animals that consumed photo-oxidized milk further supports the substantial negative influence of photo-oxidized milk on hepatic lipid metabolism. Gene set enrichment and interaction analyses revealed that photo-oxidized milk inhibited the cytochrome P450 pathway in mice, while also affecting other pathways associated with cellular stress response and lipid biosynthesis. CONCLUSION This comprehensive study provides significant evidence regarding the potential health risks associated with photo-oxidized milk, particularly in terms of hepatic oxidative damage. It establishes a scientific foundation for assessing the safety of such milk and ensuring the quality of dairy products.
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Affiliation(s)
- Sijia Tan
- Key Laboratory of Geriatric Nutrition and Health (Beijing Technology and Business University), Ministry of Education, 100048, China; Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100081, China
| | - Qiangqiang Li
- Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China.
| | - Can Guo
- Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100081, China
| | - Sumeng Chen
- China Agricultural University, Beijing 100193, China
| | - Afaf Kamal-Eldin
- College of Food and Agriculture, Department of Food, Nutrition and Health (CFA), United Arab Emirates University, Al Ain 10008115551, United Arab Emirates
| | - Gang Chen
- Key Laboratory of Geriatric Nutrition and Health (Beijing Technology and Business University), Ministry of Education, 100048, China.
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Qian F, Ouyang B, Cai Z, Zhu D, Yu S, Zhao J, Wei N, Wang G, Wang L, Zhang J. Compound Shouwu Jiangzhi Granule regulates triacylglyceride synthesis to alleviate hepatic lipid accumulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155691. [PMID: 38744232 DOI: 10.1016/j.phymed.2024.155691] [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: 12/24/2023] [Revised: 04/10/2024] [Accepted: 04/28/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with few therapeutic options currently available. Traditional Chinese medicine has been used for thousands of years and exhibited remarkable advantages against such complicated disease for its "multi-component, multi-target and multi-pathway" characteristics. Compound Shouwu Jiangzhi Granule (CSJG) is a clinical empirical prescription for the treatment of NAFLD, but its pharmacological mechanism remains unknown. METHODS The clinical efficacy of CSJG was retrospectively analyzed in NAFLD patients by comparing blood biomarkers levels and liver MR images before and after CSJG treatment. Then, high-fat/high-fructose (HFHF) diet-induced NAFLD mice were used to further confirm CSJG's effect against hepatic lipid accumulation through hepatic lipid determination and histopathological staining of liver samples. Next, the ingredients of CSJG were determined, and network pharmacology analysis was performed to predict potential targets of CSJG, followed by quantitative PCR (qPCR) and western blotting for verification. Then, lipidomics study was carried out to further explore the anti-NAFLD mechanism of CSJG from the perspective of triacylglyceride (TAG) synthesis but not free fatty acid (FFA) synthesis. The enzymes involved in this process were assayed by qPCR and western blotting. The potential interactions between the key enzymes of TAG synthesis and the active ingredients of CSJG were analyzed by molecular docking. RESULTS CSJG attenuated blood lipid levels and hepatic fat accumulation in both NAFLD patients and mice. Although network pharmacology analysis revealed the FFA synthesis pathway, CSJG only slightly affected it. Through lipidomics analysis, GSJG was found to significantly block the synthesis of diglycerides (DAGs) and TAGs in the liver, with decreased DGAT2 and increased PLD1 protein expression, which diverted DAGs from the synthesis of TAGs to the production of PEs, PCs and PAs and thus lowed TAGs level. Molecular docking suggested that rhein, luteolin and liquiritigenin from CSJG might be involved in this regulation. CONCLUSION Clinical and experimental evidence demonstrated that CSJG is a promising agent for the treatment of NAFLD. CSJG regulated TAGs synthesis to alleviate hepatic lipid accumulation. Rhein, luteolin and liquiritigenin from CSJG might play a role in it.
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Affiliation(s)
- Fei Qian
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bingchen Ouyang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China
| | - Zuhuan Cai
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China
| | - Dan Zhu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Simiao Yu
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China
| | - Jingcheng Zhao
- School of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Naijie Wei
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China
| | - Guangji Wang
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China.
| | - Lin Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University, Yantai, China.
| | - Jingwei Zhang
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, China.
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14
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Maurotti S, Geirola N, Frosina M, Mirarchi A, Scionti F, Mare R, Montalcini T, Pujia A, Tirinato L. Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma. Front Cell Dev Biol 2024; 12:1404006. [PMID: 38818407 PMCID: PMC11137176 DOI: 10.3389/fcell.2024.1404006] [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: 03/20/2024] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Over the past 10 years, the biological role of lipid droplets (LDs) has gained significant attention in the context of both physiological and pathological conditions. Considerable progress has been made in elucidating key aspects of these organelles, yet much remains to be accomplished to fully comprehend the myriad functions they serve in the progression of hepatic tumors. Our current perception is that LDs are complex and active structures managed by a distinct set of cellular processes. This understanding represents a significant paradigm shift from earlier perspectives. In this review, we aim to recapitulate the function of LDs within the liver, highlighting their pivotal role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) (Hsu and Loomba, 2024) and their contribution to the progression towards more advanced pathological stages up to hepatocellular carcinoma (HC) (Farese and Walther, 2009). We are aware of the molecular complexity and changes occurring in the neoplastic evolution of the liver. Our attempt, however, is to summarize the most important and recent roles of LDs across both healthy and all pathological liver states, up to hepatocarcinoma. For more detailed insights, we direct readers to some of the many excellent reviews already available in the literature (Gluchowski et al., 2017; Hu et al., 2020; Seebacher et al., 2020; Paul et al., 2022).
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Affiliation(s)
- Samantha Maurotti
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Nadia Geirola
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Miriam Frosina
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Angela Mirarchi
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Francesca Scionti
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Rosario Mare
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Tiziana Montalcini
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Arturo Pujia
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Luca Tirinato
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
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15
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Dawood RM, Salum GM, Abd El-Meguid M, Fotouh BES. Molecular Insights of Nonalcoholic Fatty Liver Disease Pathogenesis. J Interferon Cytokine Res 2024; 44:111-123. [PMID: 38301145 DOI: 10.1089/jir.2023.0162] [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] [Indexed: 02/03/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease. Many hepatic abnormalities are associated with NAFLD such as nonalcoholic steatohepatitis, progressive fibrosis, cirrhosis, and liver failure. Moreover, the pathogenesis of NAFLD has numerous etiologies and can be explained due to the existence of several of stimulus that act simultaneously on genetically susceptible patients. These stimuli include obesity, diabetes, and insulin resistance. In addition, identifying the role of gut microbiota on NAFLD progression has been illustrated. In this review, we clarified the several factors that lead to the development of NAFLD and identify those who are most at risk of developing liver end-stage disease. Highlighting the noninvasive diagnostic NAFLD markers could be helpful in the disease prevention and treatment approaches.
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Affiliation(s)
- Reham Mohammed Dawood
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Center, Giza, Egypt
| | - Ghada Maher Salum
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Center, Giza, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Center, Giza, Egypt
| | - Basma El-Sayed Fotouh
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Center, Giza, Egypt
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16
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Ding X, He X, Tang B, Lan T. Integrated traditional Chinese and Western medicine in the prevention and treatment of non-alcoholic fatty liver disease: future directions and strategies. Chin Med 2024; 19:21. [PMID: 38310315 PMCID: PMC10838467 DOI: 10.1186/s13020-024-00894-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/23/2024] [Indexed: 02/05/2024] Open
Abstract
Traditional Chinese medicine (TCM) has been widely used for several centuries for metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). At present, NAFLD has become the most prevalent form of chronic liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. However, there is still a lack of effective treatment strategies in Western medicine. The development of NAFLD is driven by multiple mechanisms, including genetic factors, insulin resistance, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, gut microbiota dysbiosis, and adipose tissue dysfunction. Currently, certain drugs, including insulin sensitizers, statins, vitamin E, ursodeoxycholic acid and betaine, are proven to be beneficial for the clinical treatment of NAFLD. Due to its complex pathogenesis, personalized medicine that integrates various mechanisms may provide better benefits to patients with NAFLD. The holistic view and syndrome differentiation of TCM have advantages in treating NAFLD, which are similar to the principles of personalized medicine. In TCM, NAFLD is primarily classified into five types based on clinical experience. It is located in the liver and is closely related to spleen and kidney functions. However, due to the multi-component characteristics of traditional Chinese medicine, its application in the treatment of NAFLD has been considerably limited. In this review, we summarize the advances in the pathogenesis and treatment of NAFLD, drawn from both the Western medicine and TCM perspectives. We highlight that Chinese and Western medicine have complementary advantages and should receive increased attention in the prevention and treatment of NAFLD.
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Affiliation(s)
- Xin Ding
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Xu He
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Bulang Tang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
- School of Pharmacy, Harbin Medical University, Harbin, 150086, China.
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17
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Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95:101231. [PMID: 38056058 DOI: 10.1016/j.mam.2023.101231] [Citation(s) in RCA: 53] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
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Affiliation(s)
- Maurizio Parola
- Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine - Royal Free Hospital, London, NW32PF, United Kingdom.
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18
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Radwan E, Abdelaziz A, Mandour MAM, Meki ARMA, El-Kholy MM, Mohamed MN. MBOAT7 expression is associated with disease progression in COVID-19 patients. Mol Biol Rep 2024; 51:79. [PMID: 38183501 PMCID: PMC10771377 DOI: 10.1007/s11033-023-09009-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/09/2023] [Indexed: 01/08/2024]
Abstract
BACKGROUND AND AIM The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 caused a pandemic of acute respiratory disease, named coronavirus disease 2019 (COVID-19). COVID-19 became one of the most challenging health emergencies, hence the necessity to find different prognostic factors for disease progression, and severity. Membrane bound O-acyltransferase domain containing 7 (MBOAT7) demonstrates anti-inflammatory effects through acting as a fine-tune regulator of the amount of cellular free arachidonic acid. We aimed in this study to evaluate MBOAT7 expression in COVID-19 patients and to correlate it with disease severity and outcomes. METHODS This case-control study included 56 patients with confirmed SARS-CoV-2 diagnosis and 28 control subjects. Patients were further classified into moderate (n = 28) and severe (n = 28) cases. MBOAT7, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) mRNA levels were evaluated in peripheral blood mononuclear cells (PBMC) samples isolated from patients and control subjects by real time quantitative polymerase chain reaction (RT-qPCR). In addition, circulating MBOAT7 protein levels were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS Significant lower levels of circulating MBOAT7 mRNA and protein were observed in COVID-19 patients compared to control subjects with severe COVID-19 cases showing significant lower levels compared to moderate cases. Moreover, severe cases showed a significant upregulation of TNF-α and IL-1ß mRNA. MBOAT7 mRNA and protein levels were significantly correlated with inflammatory markers (TNF-α, IL-1ß, C-reactive protein (CRP), and ferritin), liver enzymes, severity, and oxygen saturation levels. CONCLUSION COVID-19 is associated with downregulation of MBAOT7, which correlates with disease severity.
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Affiliation(s)
- Eman Radwan
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.
- Department of Biochemistry, Sphinx University, New Assiut City, Assiut 10, Egypt.
| | - Ahmed Abdelaziz
- Department of Biochemistry, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt
| | - Manal A M Mandour
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Abdel-Raheim M A Meki
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
- Department of Biochemistry, Sphinx University, New Assiut City, Assiut 10, Egypt
| | - Maha M El-Kholy
- Department of Chest diseases and Tuberculosis, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Marwan N Mohamed
- Department of Chest diseases and Tuberculosis, Faculty of Medicine, Assiut University, Assiut, Egypt
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19
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Maccali C, Pereira IVA, Stefano JT, Oliveira CP. Risk of Liver Cancer in MASLD: Role of Genetic Risk Scores. CURRENT HEPATOLOGY REPORTS 2023; 22:228-237. [DOI: 10.1007/s11901-023-00623-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/20/2023] [Indexed: 02/11/2025]
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20
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Motta BM, Masarone M, Torre P, Persico M. From Non-Alcoholic Steatohepatitis (NASH) to Hepatocellular Carcinoma (HCC): Epidemiology, Incidence, Predictions, Risk Factors, and Prevention. Cancers (Basel) 2023; 15:5458. [PMID: 38001718 PMCID: PMC10670704 DOI: 10.3390/cancers15225458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/07/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem.
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Affiliation(s)
| | | | | | - Marcello Persico
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy; (B.M.M.); (M.M.); (P.T.)
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Terracciani F, Falcomatà A, Gallo P, Picardi A, Vespasiani-Gentilucci U. Prognostication in NAFLD: physiological bases, clinical indicators, and newer biomarkers. J Physiol Biochem 2023; 79:851-868. [PMID: 36472795 DOI: 10.1007/s13105-022-00934-0] [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: 05/22/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western countries. Notably, while the majority of NAFLD patients will not evolve until advanced liver disease, a minority of them will progress towards liver-related events. Therefore, risk stratification and prognostication are emerging as fundamental in order to optimize human and economic resources for the care of these patients.Liver fibrosis has been clearly recognized as the main predictor of poor hepatic and extrahepatic outcomes. However, a prediction based only on the stage of fibrosis is near-sighted and static, as it does not capture the propensity of disease to further progress, the speed of progression and their changes over time. These determinants, which result from the interaction between genetic predisposition and acquired risk factors (obesity, diabetes, etc.), express themselves in disease activity, and can be synthesized by biomarkers of hepatic inflammation and fibrogenesis.In this review, we present the currently available clinical tools for risk stratification and prognostication in NAFLD specifically with respect to the risk of progression towards hard hepatic outcomes, i.e., liver-related events and death. We also discuss about the genetic and acquired drivers of disease progression, together with the physiopathological bases of their come into action. Finally, we introduce the most promising biomarkers in the direction of repeatedly assessing disease activity over time, mainly in response to future therapeutic interventions.
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Affiliation(s)
- Francesca Terracciani
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Andrea Falcomatà
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Paolo Gallo
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy.
| | - Antonio Picardi
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
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22
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Tian Y, Wang B. Unraveling the pathogenesis of non-alcoholic fatty liver diseases through genome-wide association studies. J Gastroenterol Hepatol 2023; 38:1877-1885. [PMID: 37592846 PMCID: PMC10693931 DOI: 10.1111/jgh.16330] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/23/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a significant health burden around the world, affecting approximately 25% of the population. Recent advances in human genetic databases have allowed for the identification of various single nucleotide polymorphisms associated with NAFLD-related traits. Investigating the functions of these genetic factors provides insight into the pathogenesis of NAFLD and potentially identifies novel therapeutic targets for NAFLD. In this review, we summarized current research on genes with NAFLD-associated mutations, highlighting phospholipid remodeling and spatially clustered loci as common pathological and genetic features of these mutations. These features suggest a complex yet intriguing mechanism of dissociated steatosis and insulin resistance, which is observed in a subset of patients and may lead to more precise therapy against NAFLD in the future.
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Affiliation(s)
- Ye Tian
- Department of Comparative Biosciences, College of Veterinary Medicine
| | - Bo Wang
- Department of Comparative Biosciences, College of Veterinary Medicine
- Division of Nutritional Sciences, College of Agricultural, Consumer and Environmental Sciences
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
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23
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Caddeo A, Spagnuolo R, Maurotti S. MBOAT7 in liver and extrahepatic diseases. Liver Int 2023; 43:2351-2364. [PMID: 37605540 DOI: 10.1111/liv.15706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 08/23/2023]
Abstract
MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.
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Affiliation(s)
- Andrea Caddeo
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Rocco Spagnuolo
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Samantha Maurotti
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
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24
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Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S. Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023; 24:53. [DOI: 10.1186/s43042-023-00433-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/21/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity.
Main body
This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD.
Conclusion
As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in clinical practice in the future.
Graphical abstract
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25
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Ronzoni L, Mureddu M, Malvestiti F, Moretti V, Bianco C, Periti G, Baldassarri M, Ariani F, Carrer A, Pelusi S, Renieri A, Prati D, Valenti L. Liver Involvement in Patients with Rare MBOAT7 Variants and Intellectual Disability: A Case Report and Literature Review. Genes (Basel) 2023; 14:1633. [PMID: 37628684 PMCID: PMC10454727 DOI: 10.3390/genes14081633] [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: 07/20/2023] [Revised: 08/08/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has been linked to steatotic liver disease susceptibility. However, the impact of biallelic loss-of-function MBOAT7 variants on liver disease is not known. We report on a 2-year-old girl with MBOAT7-related intellectual disability and steatotic liver disease, confirming that MBOAT7 loss-of-function predisposes to liver disease.
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Affiliation(s)
- Luisa Ronzoni
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Matteo Mureddu
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Francesco Malvestiti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Vittoria Moretti
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Cristiana Bianco
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Giulia Periti
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Margherita Baldassarri
- Medical Genetics, University of Siena, 53100 Siena, Italy
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Francesca Ariani
- Medical Genetics, University of Siena, 53100 Siena, Italy
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Anna Carrer
- Medical Genetics, University of Siena, 53100 Siena, Italy
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Serena Pelusi
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Alessandra Renieri
- Medical Genetics, University of Siena, 53100 Siena, Italy
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Daniele Prati
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
| | - Luca Valenti
- Biological Resource Center, and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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26
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Xu X, Xu H, Liu X, Zhang S, Cao Z, Qiu L, Du X, Liu Y, Wang G, Zhang L, Zhang Y, Zhang J. MBOAT7 rs641738 (C>T) is associated with NAFLD progression in men and decreased ASCVD risk in elder Chinese population. Front Endocrinol (Lausanne) 2023; 14:1199429. [PMID: 37424875 PMCID: PMC10324031 DOI: 10.3389/fendo.2023.1199429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Background and aim The MBOAT7 rs641738 (C>T) variant has demonstrated an association with non-alcoholic fatty liver disease (NAFLD) in both adult and pediatric patients, while few studies have been conducted in elderly populations. Hence, a case-control study was undertaken to assess their correlation in elderly residents in a Beijing community. Materials and methods A total of 1,287 participants were included. Medical history, abdominal ultrasound, and laboratory tests were recorded. Liver fat content and fibrosis stage were detected by Fibroscan. Genotyping of genomic DNA was performed using the 96.96 genotyping integrated fluidics circuit. Results Of the recruited subjects, 638 subjects (56.60%) had NAFLD, and 398 subjects (35.28%) had atherosclerotic cardiovascular disease (ASCVD). T allele carriage was associated with higher ALT (p=0.005) and significant fibrosis in male NAFLD patients (p=0.005) compared to CC genotype. TT genotype was associated with reduced risk of metabolic syndrome (OR=0.589, 95%CI: 0.114-0.683, p=0.005) and type 2 diabetes (OR=0.804, 95%CI: 0.277-0.296, p=0.048) in NAFLD population when compared to the CC genotype. In addition, TT genotype was also associated with reduced risk of ASCVD (OR=0.570, 95%CI:0.340-0.953, p=0.032) and less obesity (OR=0.545, 95%CI: 0.346-0.856, p=0.008) in the whole population. Conclusion MBOAT7 rs641738 (C>T) variant was associated with fibrosis in male NAFLD patients. The variant also reduced risk of metabolic traits and type 2 diabetes in NAFLD and ASCVD risk in Chinese elders.
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Affiliation(s)
- Xiaoyi Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hangfei Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shuang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Zhenhuan Cao
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lixia Qiu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaofei Du
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yali Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Gang Wang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Li Zhang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Yang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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27
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Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Nat Commun 2023; 14:3533. [PMID: 37316513 PMCID: PMC10267149 DOI: 10.1038/s41467-023-38932-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 05/22/2023] [Indexed: 06/16/2023] Open
Abstract
Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.
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Affiliation(s)
- Kun Wang
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Chia-Wei Lee
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Xuewu Sui
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA
| | - Siyoung Kim
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Shuhui Wang
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Aidan B Higgs
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Aaron J Baublis
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Harvard T.H. Chan Advanced Multi-Omics Platform, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Gregory A Voth
- Department of Chemistry, Chicago Center for Theoretical Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA
| | - Maofu Liao
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
- School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
| | - Tobias C Walther
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
- Harvard T.H. Chan Advanced Multi-Omics Platform, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Howard Hughes Medical Institute, Boston, MA, USA.
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Robert V Farese
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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28
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Gautam J, Kumari D, Aggarwal H, Gupta SK, Kasarla SS, Sarkar S, Priya MRK, Kamboj P, Kumar Y, Dikshit M. Characterization of lipid signatures in the plasma and insulin-sensitive tissues of the C57BL/6J mice fed on obesogenic diets. Biochim Biophys Acta Mol Cell Biol Lipids 2023:159348. [PMID: 37285928 DOI: 10.1016/j.bbalip.2023.159348] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
Diet-induced obesity mouse models are widely utilized to investigate the underlying mechanisms of dyslipidemia, glucose intolerance, insulin resistance, hepatic steatosis, and type 2 diabetes mellitus (T2DM), as well as for screening potential drug compounds. However, there is limited knowledge regarding specific signature lipids that accurately reflect dietary disorders. In this study, we aimed to identify key lipid signatures using LC/MS-based untargeted lipidomics in the plasma, liver, adipose tissue (AT), and skeletal muscle tissues (SKM) of male C57BL/6J mice that were fed chow, LFD, or obesogenic diets (HFD, HFHF, and HFCD) for a duration of 20 weeks. Furthermore, we conducted a comprehensive lipid analysis to assess similarities and differences with human lipid profiles. The mice fed obesogenic diets exhibited weight gain, glucose intolerance, elevated BMI, glucose and insulin levels, and a fatty liver, resembling characteristics of T2DM and obesity in humans. In total, we identified approximately 368 lipids in plasma, 433 in the liver, 493 in AT, and 624 in SKM. Glycerolipids displayed distinct patterns across the tissues, differing from human findings. However, changes in sphingolipids, phospholipids, and the expression of inflammatory and fibrotic genes showed similarities to reported human findings. Significantly modulated pathways in the obesogenic diet-fed groups included ceramide de novo synthesis, sphingolipid remodeling, and the carboxylesterase pathway, while lipoprotein-mediated pathways were minimally affected.
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Affiliation(s)
- Jyoti Gautam
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Deepika Kumari
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Hobby Aggarwal
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Sonu Kumar Gupta
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Siva Swapna Kasarla
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Soumalya Sarkar
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - M R Kamla Priya
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Parul Kamboj
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Yashwant Kumar
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India.
| | - Madhu Dikshit
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India.
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [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: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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30
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Odriozola A, Santos-Laso A, Del Barrio M, Cabezas J, Iruzubieta P, Arias-Loste MT, Rivas C, Duque JCR, Antón Á, Fábrega E, Crespo J. Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review. Int J Mol Sci 2023; 24:ijms24097791. [PMID: 37175497 PMCID: PMC10178387 DOI: 10.3390/ijms24097791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD.
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Affiliation(s)
- Aitor Odriozola
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Alvaro Santos-Laso
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Del Barrio
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Joaquín Cabezas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Paula Iruzubieta
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Coral Rivas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Juan Carlos Rodríguez Duque
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Ángela Antón
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Emilio Fábrega
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
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31
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Massey WJ, Varadharajan V, Banerjee R, Brown AL, Horak AJ, Hohe RC, Jung BM, Qiu Y, Chan ER, Pan C, Zhang R, Allende DS, Willard B, Cheng F, Lusis AJ, Brown JM. MBOAT7-driven lysophosphatidylinositol acylation in adipocytes contributes to systemic glucose homeostasis. J Lipid Res 2023; 64:100349. [PMID: 36806709 PMCID: PMC10041558 DOI: 10.1016/j.jlr.2023.100349] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/21/2023] Open
Abstract
We previously demonstrated that antisense oligonucleotide-mediated knockdown of Mboat7, the gene encoding membrane bound O-acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated Mboat7 floxed mice and created hepatocyte- and adipocyte-specific Mboat7 knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid-containing PI pools, Mboat7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.
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Affiliation(s)
- William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rakhee Banerjee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Amanda L Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Anthony J Horak
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rachel C Hohe
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Bryan M Jung
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Yunguang Qiu
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - E Ricky Chan
- Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Calvin Pan
- Departments of Medicine, Microbiology, and Human Genetics, University of California Los Angeles, Los Angeles, CA, USA
| | - Renliang Zhang
- Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Daniela S Allende
- Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH, USA
| | - Belinda Willard
- Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Aldons J Lusis
- Departments of Medicine, Microbiology, and Human Genetics, University of California Los Angeles, Los Angeles, CA, USA
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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Sharpe MC, Pyles KD, Hallcox T, Kamm DR, Piechowski M, Fisk B, Albert CJ, Carpenter DH, Ulmasov B, Ford DA, Neuschwander-Tetri BA, McCommis KS. Enhancing Hepatic MBOAT7 Expression in Mice With Nonalcoholic Steatohepatitis. GASTRO HEP ADVANCES 2023; 2:558-572. [PMID: 37293574 PMCID: PMC10249591 DOI: 10.1016/j.gastha.2023.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
BACKGROUND AND AIMS Polymorphisms near the membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are associated with worsened nonalcoholic fatty liver (NASH), and nonalcoholic fatty liver disease (NAFLD)/NASH may decrease MBOAT7 expression independent of these polymorphisms. We hypothesized that enhancing MBOAT7 function would improve NASH. METHODS Genomic and lipidomic databases were mined for MBOAT7 expression and hepatic phosphatidylinositol (PI) abundance in human NAFLD/NASH. Male C57BL6/J mice were fed either choline-deficient high-fat diet or Gubra Amylin NASH diet and subsequently infected with adeno-associated virus expressing MBOAT7 or control virus. NASH histological scoring and lipidomic analyses were performed to assess MBOAT7 activity, hepatic PI, and lysophosphatidylinositol (LPI) abundance. RESULTS Human NAFLD/NASH decreases MBOAT7 expression and hepatic abundance of arachidonate-containing PI. Murine NASH models display subtle changes in MBOAT7 expression, but significantly decreased activity. After MBOAT7 overexpression, liver weights, triglycerides, and plasma alanine and aspartate transaminase were modestly improved by MBOAT7 overexpression, but NASH histology was not improved. Despite confirmation of increased activity with MBOAT7 overexpression, content of the main arachidonoylated PI species was not rescued by MBOAT7 although the abundance of many PI species was increased. Free arachidonic acid was elevated but the MBOAT7 substrate arachidonoyl-CoA was decreased in NASH livers compared to low-fat controls, likely due to the decreased expression of long-chain acyl-CoA synthetases. CONCLUSION Results suggest decreased MBOAT7 activity plays a role in NASH, but MBOAT7 overexpression fails to measurably improve NASH pathology potentially due to the insufficient abundance of its arachidonoyl-CoA substrate.
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Affiliation(s)
- Martin C. Sharpe
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Kelly D. Pyles
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Taylor Hallcox
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Dakota R. Kamm
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Michaela Piechowski
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Bryan Fisk
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri
| | - Carolyn J. Albert
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | | | - Barbara Ulmasov
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri
| | - David A. Ford
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Brent A. Neuschwander-Tetri
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Kyle S. McCommis
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
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Kalafati IP, Dimitriou M, Revenas K, Kokkinos A, Deloukas P, Dedoussis GV. TM6SF2-rs58542926 Genetic Variant Modifies the Protective Effect of a "Prudent" Dietary Pattern on Serum Triglyceride Levels. Nutrients 2023; 15:1112. [PMID: 36904112 PMCID: PMC10005630 DOI: 10.3390/nu15051112] [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: 01/29/2023] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
The epidemic prevalence of non-alcoholic fatty liver disease (NAFLD), despite extensive research in the field, underlines the importance of focusing on personalized therapeutic approaches. However, nutrigenetic effects on NAFLD are poorly investigated. To this end, we aimed to explore potential gene-dietary pattern interactions in a NAFLD case-control study. The disease was diagnosed with liver ultrasound and blood collection was performed after an overnight fast. Adherence to four a posteriori, data-driven, dietary patterns was used to investigate interactions with PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and GCKR-rs738409 in disease and related traits. IBM SPSS Statistics/v21.0 and Plink/v1.07 were used for statistical analyses. The sample consisted of 351 Caucasian individuals. PNPLA3-rs738409 was positively associated with disease odds (OR = 1.575, p = 0.012) and GCKR-rs738409 with lnC-reactive protein (CRP) (beta = 0.098, p = 0.003) and Fatty Liver Index (FLI) levels (beta = 5.011, p = 0.007). The protective effect of a "Prudent" dietary pattern on serum triglyceride (TG) levels in this sample was significantly modified by TM6SF2-rs58542926 (pinteraction = 0.007). TM6SF2-rs58542926 carriers may not benefit from a diet rich in unsaturated fatty acids and carbohydrates in regard to TG levels, a commonly elevated feature in NAFLD patients.
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Affiliation(s)
- Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42100 Trikala, Greece
| | - Maria Dimitriou
- Department of Nutrition and Dietetics, School of Health Sciences, University of the Peloponnese, Antikalamos, 24100 Kalamata, Greece
| | | | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
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Villela Nogueira CA, Leite NC. Nonalcoholic Fatty Liver in the Pathogenesis of Diabetes. THE DIABETES TEXTBOOK 2023:261-270. [DOI: 10.1007/978-3-031-25519-9_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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Holmer M, Ekstedt M, Nasr P, Zenlander R, Wester A, Tavaglione F, Romeo S, Kechagias S, Stål P, Hagström H. Effect of common genetic variants on the risk of cirrhosis in non-alcoholic fatty liver disease during 20 years of follow-up. Liver Int 2022; 42:2769-2780. [PMID: 36166317 PMCID: PMC9828463 DOI: 10.1111/liv.15438] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 09/11/2022] [Accepted: 09/25/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS Several genotypes associate with a worse histopathological profile in patients with non-alcoholic fatty liver disease (NAFLD). Whether genotypes impact long-term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. METHOD DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non-alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population-based registers. Events of severe liver disease and all-cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. RESULTS In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66-8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79-4.14). After up to 40 years of follow-up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15-4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85-11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14-59.47). Overall mortality was not affected by any genetic variant. CONCLUSION The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies.
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Affiliation(s)
- Magnus Holmer
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Patrik Nasr
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden,Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Robin Zenlander
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Axel Wester
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden,Department of CardiologySahlgrenska University HospitalGothenburgSweden
| | - Stergios Kechagias
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Per Stål
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Hannes Hagström
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden,Clinical Epidemiology Unit, Department of Medicine, SolnaKarolinska InstitutetStockholmSweden
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Dong Y, Zhang Y, Feng Y, An W. The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease. Front Pharmacol 2022; 13:928606. [PMID: 36304168 PMCID: PMC9592723 DOI: 10.3389/fphar.2022.928606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) occurs in 25% of the global population and manifests as lipid deposition, hepatocyte injury, activation of Kupffer and stellate cells, and steatohepatitis. Predominantly expressed in hepatocytes, the augmenter of liver regeneration (ALR) is a key factor in liver regulation that can alleviate fatty liver disease and protect the liver from abnormal liver lipid metabolism. ALR has three isoforms (15-, 21-, and 23-kDa), amongst which 23-kDa ALR is the most extensively studied. The 23-kDa ALR isoform is a sulfhydryl oxidase that resides primarily in the mitochondrial intermembrane space (IMS), whereby it protects the liver against various types of injury. In this review, we describe the role of ALR in regulating hepatocytes in the context of NAFLD. We also discuss questions about ALR that remain to be explored in the future. In conclusion, ALR appears to be a promising therapeutic target for treating NAFLD.
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Affiliation(s)
- Yuan Dong
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yuejie Zhang
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yingmei Feng
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yingmei Feng, ; Wei An,
| | - Wei An
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, China
- *Correspondence: Yingmei Feng, ; Wei An,
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Barneda D, Janardan V, Niewczas I, Collins DM, Cosulich S, Clark J, Stephens LR, Hawkins PT. Acyl chain selection couples the consumption and synthesis of phosphoinositides. EMBO J 2022; 41:e110038. [PMID: 35771169 PMCID: PMC9475507 DOI: 10.15252/embj.2021110038] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
Phosphoinositides (PIPn) in mammalian tissues are enriched in the stearoyl/arachidonoyl acyl chain species ("C38:4"), but its functional significance is unclear. We have used metabolic tracers (isotopologues of inositol, glucose and water) to study PIPn synthesis in cell lines in which this enrichment is preserved to differing relative extents. We show that PIs synthesised from glucose are initially enriched in shorter/more saturated acyl chains, but then rapidly remodelled towards the C38:4 species. PIs are also synthesised by a distinct 're-cycling pathway', which utilises existing precursors and exhibits substantial selectivity for the synthesis of C38:4-PA and -PI. This re-cycling pathway is rapidly stimulated during receptor activation of phospholipase-C, both allowing the retention of the C38:4 backbone and the close coupling of PIPn consumption to its resynthesis, thus maintaining pool sizes. These results suggest that one property of the specific acyl chain composition of PIPn is that of a molecular code, to facilitate 'metabolic channelling' from PIP2 to PI via pools of intermediates (DG, PA and CDP-DG) common to other lipid metabolic pathways.
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Affiliation(s)
- David Barneda
- Signalling Programme, Babraham Institute, Cambridge, UK.,Projects, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Vishnu Janardan
- Cellular Organization and Signalling, National Centre for Biological Sciences, Bangalore, India
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Varadharajan V, Massey WJ, Brown JM. Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease. J Lipid Res 2022; 63:100234. [PMID: 35636492 PMCID: PMC9240865 DOI: 10.1016/j.jlr.2022.100234] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Advanced liver diseases account for approximately 2 million deaths annually worldwide. Roughly, half of liver disease-associated deaths arise from complications of cirrhosis and the other half driven by viral hepatitis and hepatocellular carcinoma. Unfortunately, the development of therapeutic strategies to treat subjects with advanced liver disease has been hampered by a lack of mechanistic understanding of liver disease progression and a lack of human-relevant animal models. An important advance has been made within the past several years, as several genome-wide association studies have discovered that an SNP near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) is associated with severe liver diseases. This common MBOAT7 variant (rs641738, C>T), which reduces MBOAT7 expression, confers increased susceptibility to nonalcoholic fatty liver disease, alcohol-associated liver disease, and liver fibrosis in patients chronically infected with viral hepatitis. Recent studies in mice also show that Mboat7 loss of function can promote hepatic steatosis, inflammation, and fibrosis, causally linking this phosphatidylinositol remodeling enzyme to liver health in both rodents and humans. Herein, we review recent insights into the mechanisms by which MBOAT7-driven phosphatidylinositol remodeling influences liver disease progression and discuss how rapid progress in this area could inform drug discovery moving forward.
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Affiliation(s)
- Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications. J Clin Med 2022; 11:jcm11133649. [PMID: 35806934 PMCID: PMC9267803 DOI: 10.3390/jcm11133649] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/09/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome’s extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD–IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches.
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Yan LS, Zhang SF, Luo G, Cheng BCY, Zhang C, Wang YW, Qiu XY, Zhou XH, Wang QG, Song XL, Pan SY, Zhang Y. Schisandrin B mitigates hepatic steatosis and promotes fatty acid oxidation by inducing autophagy through AMPK/mTOR signaling pathway. Metabolism 2022; 131:155200. [PMID: 35405150 DOI: 10.1016/j.metabol.2022.155200] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/05/2022] [Accepted: 03/31/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Schisandrin B (Sch B), which inhibits hepatic steatosis caused by non-alcoholic fatty liver disease (NAFLD), is one of the most active dibenzocyclooctadienes isolated from Schisandra chinensis (Turcz.) Baill with various pharmacological activities. In this study, the role of Sch B-induced autophagy in lipid-lowering activities of Sch B was examined and the underlying mechanisms were elucidated. METHODS Free fatty acid (FFA)-stimulated HepG2 cells and mouse primary hepatocytes (MPHs) and high-fat diet (HFD)-fed mice were used as NAFLD models. The role of Sch B-induced autophagy in lipid-lowering effects of Sch B was assessed using ATG5/TFEB-deficient cells and 3-methyladenine (3-MA)-treated hepatocytes and mice. RESULTS Sch B simultaneously active autophagy through AMPK/mTOR pathway and decreased the number of lipid droplets in FFA-treated HepG2 cells and MPHs. Additionally, siATG5/siTFEB transfection or 3-MA treatment mitigated Sch B-induced autophagy and activation of fatty acid oxidation (FAO) and ketogenesis in FFA-treated HepG2 cells and MPHs. Sch B markedly decreased hepatic lipid content and activated the autophagy through AMPK/mTOR pathway in HFD-fed mice. However, the activities of Sch B were suppressed upon 3-MA treatment. Sch B upregulated the expression of key enzymes involved in FAO and ketogenesis, which was mitigated upon 3-MA treatment. Moreover, changes in hepatic lipid components and amino acids may be related to the Sch B-induced autophagy pathway. CONCLUSION These results suggested that Sch B inhibited hepatic steatosis and promoted FAO by activation of autophagy through AMPK/mTOR pathway. Our study provides novel insights into the hepatic lipophagic activity of Sch B and its potential application in the management of NAFLD.
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Affiliation(s)
- Li-Shan Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuo-Feng Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Gan Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Brian Chi-Yan Cheng
- College of Professional and Continuing Education, Hong Kong Polytechnic University, Hong Kong, China
| | - Chao Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yi-Wei Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xin-Yu Qiu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Hong Zhou
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
| | - Qing-Gao Wang
- First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xue-Lan Song
- School of Traditional Dai-Thai Medicine, West Yunnan University of Applied Sciences, Jinghong, Yunnan, China
| | - Si-Yuan Pan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; School of Traditional Dai-Thai Medicine, West Yunnan University of Applied Sciences, Jinghong, Yunnan, China
| | - Yi Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
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Li H, Liang J, Han M, Wang X, Ren Y, Wang Y, Huang J, Li S, Liu C, Wang Z, Yue T, Gao Z. Sequentially fermented dealcoholized apple juice intervenes fatty liver induced by high-fat diets via modulation of intestinal flora and gene pathways. Food Res Int 2022; 156:111180. [DOI: 10.1016/j.foodres.2022.111180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/18/2022] [Accepted: 03/20/2022] [Indexed: 11/04/2022]
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Speliotes EK, George J. Metabolic and genetic contributions to NAFLD: Really distinct and homogeneous? J Hepatol 2022; 76:498-500. [PMID: 34979132 DOI: 10.1016/j.jhep.2021.12.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/21/2022]
Affiliation(s)
- Elizabeth K Speliotes
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW 2145, Australia.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. It refers to a range of liver conditions affecting people who drink little or no alcohol. NAFLD comprises non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. NASH is featured by steatosis, lobular inflammation, hepatocyte injury, and various degrees of fibrosis. Although much progress has been made over the past decades, the pathogenic mechanism of NAFLD remains to be fully elucidated. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear hormone receptor that is highly expressed in hepatocytes. Hepatic HNF4α expression is markedly reduced in NAFLD patients and mouse models of NASH. HNF4α has been shown to regulate bile acid, lipid, glucose, and drug metabolism. In this review, we summarize the recent advances in the understanding of the pathogenesis of NAFLD with a focus on the regulation of HNF4α and the role of hepatic HNF4α in NAFLD. Several lines of evidence have shown that hepatic HNF4α plays a key role in the initiation and progression of NAFLD. Recent data suggest that hepatic HNF4α may be a promising target for treatment of NAFLD.
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Single Nucleotide Polymorphism of Genes Associated with Metabolic Fatty Liver Disease. JOURNAL OF ONCOLOGY 2022; 2022:9282557. [PMID: 35154322 PMCID: PMC8831055 DOI: 10.1155/2022/9282557] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 02/08/2023]
Abstract
Aims The present study aimed to reveal the relationship between single nucleotide polymorphism (SNP) of PNPLA3, TM6SF2, MBOAT7, GATAD2A, and STAT3 genes and metabolism-related fatty liver disease (MAFLD), so as to provide a research basis for further exploring the diagnosis and treatment of diseases at the molecular level. Methods A total of 564 patients were included in the physical examination center of Xinjiang Karamay People's Hospital. They were divided into an MAFLD case group and a healthy control group. The whole blood DNA of each sample was extracted by a whole blood genomic DNA extraction kit, and the genotypes of PNPLA3 rs738409, MBOAT7 rs64173, STAT3 rs744166, TM6SF2 rs58542926, and GATAD2A rs4808199 were performed; after adjusting for confounding factors, the additive model, dominant model, and recessive model of each gene were analyzed by multivariate logistic regression. Results The CC genotype of the PNPLA3 gene rs738409 and the TT genotype of the MBOAT7 gene rs64173 are risk factors in the occurrence of MAFLD. The AA genotype of the STAT3 gene rs744166 is a protective factor of MAFLD, while TM6SF2 rs58542926 and GATAD2A rs4808199 show no significant correlation with MAFLD.
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Parameswaran M, Hasan HA, Sadeque J, Jhaveri S, Avanthika C, Arisoyin AE, Dhanani MB, Rath SM. Factors That Predict the Progression of Non-alcoholic Fatty Liver Disease (NAFLD). Cureus 2021; 13:e20776. [PMID: 35111461 PMCID: PMC8794413 DOI: 10.7759/cureus.20776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of diseases involving the deposition of fat in the hepatocytes of people with little to no alcohol consumption. NAFLD is associated with hypertension, diabetes, obesity, etc. As their prevalence increases, the propensity and severity of NAFLD might increase. As per the recently developed multi-hit hypothesis, factors like oxidative stress, genetic predisposition, lipotoxicity, and insulin resistance have been found to play a key role in the development of NAFLD and its associated complications. This article focuses on NAFLD, its pathophysiology, risk factors, and the various genetic and epigenetic factors involved in its development along with possible treatment modalities. We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: “NAFLD,” “NASH,” “Fibrosis,” and “Insulin Resistance.” We explored the literature on NAFLD for its epidemiology, pathophysiology, the role of various genes, and how they influence the disease and associated complications about the disease and its hepatic and extrahepatic complications. With its rapidly increasing prevalence rates across the world and serious complications like NASH and hepatocellular carcinoma, NAFLD is becoming a major public health issue and more research is needed to formulate better screening tools and treatment protocols.
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Affiliation(s)
| | | | - Jafor Sadeque
- Internal Medicine, Al Mostaqbal Hospital, Jeddah, SAU
| | - Sharan Jhaveri
- Internal Medicine, Smt. Nathiba Hargovandas Lakhmichand Municipal Medical College, Ahmedabad, IND
| | | | | | - Maulik B Dhanani
- Internal Medicine, Southwestern University School of Medicine, Cebu City, PHL
| | - Swaroopa M Rath
- Medicine, Srirama Chandra Bhanja Medical College and Hospital, Cuttack, IND
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TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cell Mol Gastroenterol Hepatol 2021; 13:759-788. [PMID: 34823063 PMCID: PMC8783129 DOI: 10.1016/j.jcmgh.2021.11.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. METHODS NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). RESULTS In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed microvesicular/macrovesicular pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum and mitochondria ultrastructures, thus increasing endoplasmic reticulum/oxidative stress. The mitochondrial number was increased in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reversed the metabolic and tumorigenic features observed in the compound knockout model. CONCLUSIONS The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC. Biomedicines 2021; 9:1524. [PMID: 34829753 PMCID: PMC8614742 DOI: 10.3390/biomedicines9111524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients' health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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49
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Mattos ÂZ, Debes JD, Dhanasekaran R, Benhammou JN, Arrese M, Patrício ALV, Zilio AC, Mattos AA. Hepatocellular carcinoma in nonalcoholic fatty liver disease: A growing challenge. World J Hepatol 2021; 13:1107-1121. [PMID: 34630878 PMCID: PMC8473502 DOI: 10.4254/wjh.v13.i9.1107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/21/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, and its prevalence increases continuously. As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis, it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise. Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver, and they help explain why liver cancer develops even in patients without cirrhosis. Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population. Currently, it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo (with or without alpha-fetoprotein), but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease. Moreover, the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases. Furthermore, it is not clear which subgroups of patients without cirrhosis should undergo surveillance. Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals. By improving surveillance, tumors could be detected in earlier stages, amenable to curative treatments.
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Affiliation(s)
- Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil.
| | - Jose D Debes
- Department of Medicine, Division of Infectious Diseases and of Gastroenterology, University of Minnesota, Minneapolis, MN 55455, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam 3015 CN, South Holland, Netherlands
| | - Renu Dhanasekaran
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, United States
| | - Jihane N Benhammou
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, CA 90095, United States
| | - Marco Arrese
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
| | - André Luiz V Patrício
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Amanda C Zilio
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
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