1-2-dilauroylphosphatidylcholine and Disease-Models--Animal

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.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Cell Line; Disease Models, Animal; Fatty Liver; HeLa Cells; Homeostasis; Humans; Hypoglycemic Agents; Insulin Resistance; Ligands; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphatidylcholines; Protein Binding; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Triglycerides