A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

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Abstract
Excess liver fat, or steatosis, is an important risk factor for obesity-associated diabetes. A natural product, dilauroyl phosphatidylcholine (DLPC), has now been identified as a possible antisteatosis agent, with therapeutic potential in pre-diabetic people. DLPC activates the orphan nuclear receptor LRH-1, loss of which decreases bile acid levels. Elevated bile acid is known to decrease steatosis. Acting as an LHR-1 agonist, DLPC decreases hepatic steatosis and improves glucose homeostasis in mouse models of insulin resistance. Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis1,2. Structural studies have identified phospholipids as potential LRH-1 ligands3,4,5, 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.