Abstract 281: Hepatic Liver Receptor Homolog-1, a Key Regulator of Lipid Storage and Phospholipid Diversity

Abstract

Cardiovascular disease and malignancy are the most common cause of death in Non-alcoholic Steatohepatitis (NASH) patients. Aside from lifestyle modification, there is currently no treatment for NASH. Activation of Liver Receptor Homolog-1 (Lrh-1), known to bind phospholipid ligands, has been shown to effectively reduce liver triglyceride (TG) in DIO mice, raising Lrh-1 as a possible target for treating NASH. Despite this finding, hepatic TGs are equivalent in controls and liver-specific Lrh-1 knockout (LKO or Lrh1 AlbCre ) mice, regardless of diet. Given this discrepancy, we sought to characterize Lrh-1’s role in hepatic lipid metabolism by acutely deleting Lrh-1 in the adult liver, thus eliminating potential compensatory developmental effects associated with LKO. To acutely eliminate Lrh-1 in hepatocytes, 6-week old Lrh-1 fl/f l male mice were infected with AVV8-TBG-eGFP (Control) or AAV8-TBG-Cre (LKO AAVCre ) via retro-orbital injection and fed chow or high fat diet. LKO AAVCre mice developed hepatic steatosis after six weeks on standard chow or high fat diet. Furthermore, LKO AAVCre hepatocytes exhibited large lipid droplets, which were visible as early as 2 wks post-infection, thus suggesting that lipid handling is significantly altered in LKO AAVCre hepatocytes, independent of fatty acid transport or oxidation. LKO AAVCre exhibited lower Pcsk9 expression, which correlated with decreased fasting plasma LDL-C. Consistent with other studies showing that perturbations in phospholipid pools affect lipid storage, lipidomic analyses revealed a significant reduction in phospholipid species containing arachidonic acid (AA), thus reducing the overall diversity of key membrane phospholipids. RNA-Seq analyses from LKO AAVCre livers confirmed that factors promoting lipid droplet size ( Cidec , Plin4 ) were greatly increased while key enzymes in biosynthesis of unsaturated fatty acids were reduced ( Fads1, Fads2 and Elovl5 ). In addition, expression of human LRH-1 in LKO AAVCre decreased hepatic TG and improved glucose tolerance in DIO mice, in a ligand dependent manner. Collectively our data establish a novel role for Lrh-1 as a key regulator of lipid storage, thereby providing the first in vivo evidence as to why phospholipid serve as Lrh-1 ligands.