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.
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We thank S. A. Kliewer and D. J. Mangelsdorf (UT Southwestern Medical Center) for the gift of Lrh-1f/f mice, A. J. Cooney for the OCT4 promoter constructs, C. Mills and D. Kuruvilla for experimental assistance, the Baylor College of Medicine Diabetes Endocrine Research Center (supported by NIH DK-079638 and USDA ARS 6250-52000-055) and the services of the Mouse Metabolism Core for hyperinsulinaemic clamp studies, and the current and previous members of the D.D.M. laboratory for discussions and technical support. Supported by NIH R01 DK068804, the Alkek Foundation and the Robert R. P. Doherty Jr—Welch Chair in Science to D.D.M., and NIH R01 CA134873 to P.R.G.
The authors declare no competing financial interests.
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Lee, J., Lee, Y., Mamrosh, J. et al. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474, 506–510 (2011). https://doi.org/10.1038/nature10111
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