Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation
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 (LP...
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| Published in | Hepatology Vol. 81; no. 2; pp. 576 - 590 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English Japanese |
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United States
Ovid Technologies (Wolters Kluwer Health)
01.02.2025
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0270-9139 1527-3350 1527-3350 |
| DOI | 10.1097/hep.0000000000000933 |
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| Abstract | 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.
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.
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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| AbstractList | 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.
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.
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. 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.BACKGROUND AND AIMSThe 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.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.APPROACH AND RESULTSWe 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.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.CONCLUSIONSThis 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. |
| Author | Hongxue Shi Peter Tontonoz Danish Saleheen Junken Aoki Shareef Khalid Luisa Ronzoni Katherine P. Yates Jerome I. Rotter Xiuqing Guo Alessandro Cherubini Naga P. Chalasani Ira Tabas Xiaobo Wang Yuki Ishino John Paul Kennelly Matthew A. Mitsche Luca Valenti Nozomu Kono Mary P. Moore Kuniyuki Kano |
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Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan – sequence: 6 givenname: Kuniyuki surname: Kano fullname: Kano, Kuniyuki organization: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan – sequence: 7 givenname: Junken surname: Aoki fullname: Aoki, Junken organization: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan – sequence: 8 givenname: Alessandro surname: Cherubini fullname: Cherubini, Alessandro organization: Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan, Italy – sequence: 9 givenname: Luisa surname: Ronzoni fullname: Ronzoni, Luisa organization: Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan, Italy – sequence: 10 givenname: Xiuqing surname: Guo fullname: Guo, Xiuqing organization: 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 – sequence: 11 givenname: Naga P. surname: Chalasani fullname: Chalasani, Naga P. organization: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA – sequence: 12 givenname: Shareef surname: Khalid fullname: Khalid, Shareef organization: Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA, Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan – sequence: 13 givenname: Danish surname: Saleheen fullname: Saleheen, Danish organization: Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA, Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan – sequence: 14 givenname: Matthew A. surname: Mitsche fullname: Mitsche, Matthew A. organization: Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA – sequence: 15 givenname: Jerome I. surname: Rotter fullname: Rotter, Jerome I. organization: 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 – sequence: 16 givenname: Katherine P. surname: Yates fullname: Yates, Katherine P. organization: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA – sequence: 17 givenname: Luca surname: Valenti fullname: Valenti, Luca organization: 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 – sequence: 18 givenname: Nozomu surname: Kono fullname: Kono, Nozomu organization: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan – sequence: 19 givenname: Peter surname: Tontonoz fullname: Tontonoz, Peter organization: Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA – sequence: 20 givenname: Ira orcidid: 0000-0003-3429-1515 surname: Tabas fullname: Tabas, Ira organization: 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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| SubjectTerms | Acyltransferases - genetics Acyltransferases - metabolism Adaptor Proteins, Signal Transducing Animals Disease Models, Animal Genetic Predisposition to Disease Hepatocytes - metabolism Humans Liver Cirrhosis - etiology Liver Cirrhosis - genetics Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Male Membrane Proteins Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease - genetics Trans-Activators - metabolism Transcriptional Coactivator with PDZ-Binding Motif Proteins Up-Regulation |
| Title | Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation |
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