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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Change history
29 May 2011
Fig. 3c was corrected.
References
Mataki, C. et al. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of the liver receptor homolog 1. Mol. Cell. Biol. 27, 8330–8339 (2007)
Lee, Y. K. et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol. Endocrinol. 22, 1345–1356 (2008)
Krylova, I. N. et al. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120, 343–355 (2005)
Ortlund, E. A. et al. Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nature Struct. Mol. Biol. 12, 357–363 (2005)
Wang, W. et al. The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1. Proc. Natl Acad. Sci. USA 102, 7505–7510 (2005)
Cusi, K. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr. Opin. Endocrinol. Diabetes Obes. 16, 141–149 (2009)
Watanabe, M. et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113, 1408–1418 (2004)
Lee, Y. K., Parker, K. L., Choi, H. S. & Moore, D. D. Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers. J. Biol. Chem. 274, 20869–20873 (1999)
Gu, P. et al. Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol. Cell. Biol. 25, 3492–3505 (2005)
Lee, Y. K., Choi, Y. H., Chua, S., Park, Y. J. & Moore, D. D. Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation. J. Biol. Chem. 281, 7850–7855 (2006)
Chalkiadaki, A. & Talianidis, I. SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin. Mol. Cell. Biol. 25, 5095–5105 (2005)
Chakravarthy, M. F. et al. Identification of a physiologically relevant endogenous ligand for PPARα in liver. Cell 138, 476–488 (2009)
Li, Y. et al. Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol. Cell 17, 491–502 (2005)
Sablin, E. P. et al. Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol. Endocrinol. 23, 25–34 (2009)
Kang, H. W., Wei, J. & Cohen, D. E. PC-TP/StARD2: Of membranes and metabolism. Trends Endocrinol. Metab. 21, 449–456 (2010)
Hunt, A. N. Dynamic lipidomics of the nucleus. J. Cell. Biochem. 97, 244–251 (2006)
Whitby, R. J. et al. Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1. J. Med. Chem. 49, 6652–6655 (2006)
Li, D. et al. Cyclic AMP-stimulated interaction between steroidogenic factor-1 and diacylglycerol kinase θ facilitates induction of CYP17. Mol. Cell Biol. 27,. 6669–6685 (2007)
Urs, A. N., Dammer, E. & Sewer, M. B. Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology 147, 5249–5258 (2006)
Lee, H. et al. Role for peroxisome proliferator-activated receptor α in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ. Res. 87, 516–521 (2000)
McIntyre, T. M. et al. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist. Proc. Natl Acad. Sci. USA 100, 131–136 (2003)
Amemiya-Kudo, M. et al. Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J. Biol. Chem. 275, 31078–31085 (2000)
Kanayama, T. et al. Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities. J. Biol. Chem. 282, 10290–10298 (2007)
Shimomura, I. et al. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc. Natl Acad. Sci. USA 96, 13656–13661 (1999)
McGarry, J. D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258, 766–770 (1992)
Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 3441–3446 (2010)
Kim, K. H. Regulation of mammalian acetyl-coenzyme A carboxylase. Annu. Rev. Nutr. 17, 77–99 (1997)
Savage, D. B. et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J. Clin. Invest. 116, 817–824 (2006)
Dong, B. et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc. Natl Acad. Sci. USA 106, 18831–18836 (2009)
Dobrzyn, P. et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc. Natl Acad. Sci. USA 101, 6409–6414 (2004)
Vidovic´, D., Busby, S. A., Griffin, P. R. & Schurer, S. C. A combined ligand- and structure-based virtual screening protocol identifies submicromolar PPARγ partial agonists. ChemMedChem 6, 94–103 (2011)
Ma, K., Saha, P. K., Chan, L. & Moore, D. D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006)
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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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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DOI: https://doi.org/10.1038/nature10111
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