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JCI Insight. 2018 Mar 8;3(5). pii: 96151. doi: 10.1172/jci.insight.96151.

LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity.

Author information

1
Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA.
2
Department of Biochemistry, Yong Loo Lin School of Medicine and Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore.
3
Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California, USA.
4
Signature Research Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore, Singapore.

Abstract

Excess lipid accumulation is an early signature of nonalcoholic fatty liver disease (NAFLD). Although liver receptor homolog 1 (LRH-1) (encoded by NR5A2) is suppressed in human NAFLD, evidence linking this phospholipid-bound nuclear receptor to hepatic lipid metabolism is lacking. Here, we report an essential role for LRH-1 in hepatic lipid storage and phospholipid composition based on an acute hepatic KO of LRH-1 in adult mice (LRH-1AAV8-Cre mice). Indeed, LRH-1-deficient hepatocytes exhibited large cytosolic lipid droplets and increased triglycerides (TGs). LRH-1-deficient mice fed high-fat diet displayed macrovesicular steatosis, liver injury, and glucose intolerance, all of which were reversed or improved by expressing wild-type human LRH-1. While hepatic lipid synthesis decreased and lipid export remained unchanged in mutants, elevated circulating free fatty acid helped explain the lipid imbalance in LRH-1AAV8-Cre mice. Lipidomic and genomic analyses revealed that loss of LRH-1 disrupts hepatic phospholipid composition, leading to lowered arachidonoyl (AA) phospholipids due to repression of Elovl5 and Fads2, two critical genes in AA biosynthesis. Our findings reveal a role for the phospholipid sensor LRH-1 in maintaining adequate pools of hepatic AA phospholipids, further supporting the idea that phospholipid diversity is an important contributor to healthy hepatic lipid storage.

KEYWORDS:

Diabetes; Hepatology; Metabolism

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