Low MBOAT7 expression, a genetic risk for MASH, promotes a... : Hepatology (original) (raw)

Original Articles: Steatohepatitis

Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation

Moore, Mary P.1; Wang, Xiaobo1; Kennelly, John Paul2; Shi, Hongxue1; Ishino, Yuki3; Kano, Kuniyuki3; Aoki, Junken3; Cherubini, Alessandro4; Ronzoni, Luisa4; Guo, Xiuqing5; Chalasani, Naga P.6; Khalid, Shareef1,7; Saleheen, Danish1,7; Mitsche, Matthew A.8; Rotter, Jerome I.5; Yates, Katherine P.9; Valenti, Luca4,10; Kono, Nozomu3; Tontonoz, Peter2; Tabas, Ira1,11,12,13

1Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA

2Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA

3Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

4Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan, Italy

5The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA

6Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

7Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan

8Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

9Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

10Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy

11Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA

12Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York, USA

13Columbia University Digestive and Liver Disease Research Center, New York, NY

Abbreviations: AGPAT1, 1-acylglycerol-3-phosphate _O_-acyltransferase 1; ALOD4, anthrolysin O domain 4; CDS2, CDP-diacylglycerol (DAG) synthase-2; DAG, diacylglycerol; FPC, fructose-palmitate-cholesterol diet; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; LoF, loss-of-function; LPI, lysophosphatidylinositol; MβCD, methyl-β-cyclodextrin; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MBOAT7, membrane bound _O_-acyltransferase domain containing 7; PC, phosphatidylcholine; PI, phosphatidylinositol; PL, phospholipid; PM, plasma membrane; PNPLA3, patatin-like phospholipase domain-containing 3; PS, phosphatidylserine; PSS1, PS synthase-1.

Mary P. Moore and Xiaobo Wang equally contributed to this work.

Correspondence Mary P. Moore, Department of Medicine, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Email: [email protected] Xiaobo Wang, Department of Medicine, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Email: [email protected] Ira Tabas, Department of Medicine, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Email: [email protected]

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.hepjournal.com.

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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.