Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid–defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 d without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides against Coenzyme A synthase ( Coasy ) or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that Coenzyme A synthase knockdown and bempedoic acid are therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Ikki Sakuma
Department of Internal Medicine, Yale School of Medicine
Rafael C. Gaspar
Department of Cellular & Molecular Physiology, Yale University
Ali R. Nasiri
Department of Internal Medicine, Yale School of Medicine
Sylvie Dufour
Department of Internal Medicine, Yale School of Medicine
Mario Kahn
Department of Internal Medicine, Yale School of Medicine
Jie Zheng
Key Laboratory of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology
Traci E. LaMoia
Department of Internal Medicine, Yale School of Medicine
Mateus T. Guerra
Department of Internal Medicine, Yale School of Medicine
Yuki Taki
Department of Molecular Diagnosis, Chiba University Graduate School of Medicine
Yusuke Kawashima
Department of Applied Genomics, Kazusa deoxyribonucleic acid Research Institute
Dean Yimlamai
Department of Pediatrics, Yale School of Medicine
Mark Perelis
Ionis Pharmaceuticals
Daniel F. Vatner
Department of Internal Medicine, Yale School of Medicine
Kitt Falk Petersen
Department of Internal Medicine, Yale School of Medicine
Maximilian Huttasch
Institute for Clinical Diabetology, German Diabetes Center (Deutsches Diabetes-Zentrum), Leibniz Center for Diabetes Research at Heinrich Heine University
Birgit Knebel
German Center for Diabetes Research (Deutsche Zentrum für Diabetesforschung e.V.), Partner Düsseldorf
Sabine Kahl
Institute for Clinical Diabetology, German Diabetes Center (Deutsches Diabetes-Zentrum), Leibniz Center for Diabetes Research at Heinrich Heine University
Michael Roden
Institute for Clinical Diabetology, German Diabetes Center (Deutsches Diabetes-Zentrum), Leibniz Center for Diabetes Research at Heinrich Heine University
Varman T. Samuel
Department of Internal Medicine, Yale School of Medicine
Tomoaki Tanaka
Department of Molecular Diagnosis, Chiba University Graduate School of Medicine
Gerald I. Shulman
Department of Internal Medicine, Yale School of Medicine