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Author Notes:

Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA Manish C. Pathak & Eric A. Ortlund.

J.M.L. designed and executed the experiments, interpreted data and cowrote the manuscript.

Y.K.L. and J.L.M. helped with experiments.

S.A.B. and P.R.G. performed the fluorescence binding experiments, and M.C.P. and E.A.O. performed the mass spectrometry experiment. D.D.M. supervised the design and interpretation of the experiments and cowrote the manuscript.

The authors declare no competing financial interests.

Subjects:

Research Funding:

We thank Steven A. Kliewer and David J. Mangelsdorf (UT Southwestern Medical Center) for the generous gift of Lrh-1f/f mice, Austin J. Cooney for the Oct4 promoter constructs, Charity Mills and Dana Kuruvilla for experimental assistance, the BCM Diabetes Endocrine Research Center (supported by NIH DK-079638) and the services of the Mouse Metabolism Core for hyperinsulinemic clamp studies, and the current and previous members of the Moore laboratory for helpful 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.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • STEROIDOGENIC FACTOR-I
  • FATTY LIVER-DISEASE
  • ORPHAN RECEPTORS
  • LRH-1
  • IDENTIFICATION
  • HOMOLOG-1
  • PHOSPHOLIPIDS
  • LIGANDS
  • BINDING
  • SHP

Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1

Tools:

Journal Title:

Nature

Volume:

Volume 474, Number 7352

Publisher:

, Pages 506-U135

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis 1,2 . Structural studies have identified phospholipids as potential LRH-1 ligands 3-5 , 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.

Copyright information:

© 2011 Macmillan Publishers Limited. All rights reserved.

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