A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Abstract

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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Figure 1: DLPC activates and binds human LRH-1.
Figure 2: DLPC and DUPC modulate expression of LRH-1 target genes in liver.
Figure 3: DLPC improves glucose homeostasis in mouse models of insulin resistance.
Figure 4: DLPC reduces liver fat accumulation by suppressing lipogenesis.

Change history

  • 29 May 2011

    Fig. 3c was corrected.

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Acknowledgements

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.

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J.M.L. designed and executed the experiments, interpreted data and co-wrote 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 co-wrote the manuscript.

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Correspondence to David D. Moore.

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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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