Journal
JOURNAL OF HEPATOLOGY
Volume 56, Issue 4, Pages 987-989Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2011.10.002
Keywords
NAFLD; Steatohepatitis; NR5A2; LRH-1; Insulin resistance
Categories
Funding
- Higher Education Funding Council for England (HEFCE)
- European Union [FP7/2007-2013, Health-F2-2009-241762]
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Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis. (C) 2011 European Association for the Study of the Liver. Published by Elsevier By. All rights reserved.
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