|Lee, Jae Man -|
|Lee, Yoon Kwang -|
|Mamrosh, Jennifer -|
|Busby, Scott -|
|Griffin, Patrick -|
|Pathak, Manish -|
|Ortlund, Eric -|
|Moore, David -|
Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 25, 2011
Publication Date: June 23, 2011
Citation: Lee, J., Lee, Y., Mamrosh, J.L., Busby, S.A., Griffin, P.R., Pathak, M.C., Ortlund, E.A., Moore, D.D. 2011. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature. 474(23):506-510. Interpretive Summary: 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. This project studied the potential role of the orphan nuclear receptor LRH-1 in metabolic regulation. We discovered that LRH-1 can be specifically activated by dilauroyl phosphatidylcholine (DLPC), an unusual phospholipid. Treatment of mouse models of insulin resistance with DLPC improved their metabolic profile, which was associated with decreased fat accumulation in the liver. This research identified a new target for treating type 2 diabetes and the metabolic syndrome. A human clinical trial testing the antidiabetic effects of DLPC is underway.
Technical Abstract: 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.