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A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Academic Article
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Overview

authors

  • Lee, Jiing-Dwan
  • Lee, Y. K.
  • Mamrosh, J. L.
  • Busby, S. A.
  • Griffin, Patrick
  • Pathak, M. C.
  • Ortlund, E. A.
  • Moore, D. D.

publication date

  • June 2011

journal

  • Nature  Journal

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.

subject areas

  • Animals
  • Bile Acids and Salts
  • Blood Glucose
  • Cell Line
  • Disease Models, Animal
  • Fatty Liver
  • HeLa Cells
  • Homeostasis
  • Humans
  • Hypoglycemic Agents
  • Insulin Resistance
  • Ligands
  • Lipogenesis
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylcholines
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear
  • Signal Transduction
  • Triglycerides
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Identity

PubMed Central ID

  • PMC3150801

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature10111

PubMed ID

  • 21614002
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Additional Document Info

start page

  • 506

end page

  • 510

volume

  • 474

issue

  • 7352

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