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LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity
Diego A. Miranda, … , David L. Silver, Holly A. Ingraham
Diego A. Miranda, … , David L. Silver, Holly A. Ingraham
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e96151. https://doi.org/10.1172/jci.insight.96151.
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Research Article Hepatology Metabolism

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

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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.

Authors

Diego A. Miranda, William C. Krause, Amaury Cazenave-Gassiot, Miyuki Suzawa, Hazel Escusa, Juat Chin Foo, Diyala S. Shihadih, Andreas Stahl, Mark Fitch, Edna Nyangau, Marc Hellerstein, Markus R. Wenk, David L. Silver, Holly A. Ingraham

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Figure 1

Deleting LRH-1 in adult liver promotes hepatic lipid accumulation.

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Deleting LRH-1 in adult liver promotes hepatic lipid accumulation.
(A) R...
(A) Relative expression by qPCR analysis of Lrh-1, Cyp8b1, and Shp in livers or primary hepatocytes isolated from Lrh-1AAV8-GFP and Lrh-1AAV8-Cre male mice or from age-matched Lrh-1fl/fl or Lrh-1Alb-Cre mice (n = 5 and n = 6 for Lrh-1AAV8-GFP and Lrh-1AAV8-Cre mice, respectively, and n = 3 for both Lrh-1fl/fl and Lrh-1Alb-cre mice). (B) TG content in livers or primary hepatocytes at two time points after infection (PI) from male mice with groups indicated in the figure. (C) Representative images (original magnification, ×20) of H&E-stained livers from Lrh-1AAV8-Cre and Lrh-1Alb-Cre mice; yellow arrows highlight lipid droplets in Lrh-1AAV8-Cre liver. For primary hepatocytes n = 2 for all genotypes or groups done in triplicate. Error bars represent ± SEM. For box-and-whisker plots, maximum and minimum values are shown with median. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired Student’s t tests.

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