Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver

Manu V. Chakravarthy, Irfan J. Lodhi, Li Yin, Raghu R.V. Malapaka, H. Eric Xu, John Turk, Clay F. Semenkovich

Research output: Contribution to journalArticlepeer-review

380 Scopus citations

Abstract

The nuclear receptor PPARα is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARα-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARα ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARα isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPARα agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPARα-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPARα ligand-binding domain and coactivator peptide motifs was comparable to PPARα agonists, but interactions with PPARδ were weak and none were detected with PPARγ. Portal vein infusion of 16:0/18:1-GPC induced PPARα-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPARα ligand.

Original languageEnglish
Pages (from-to)476-488
Number of pages13
JournalCell
Volume138
Issue number3
DOIs
StatePublished - Aug 7 2009

Keywords

  • HUMDISEASE
  • PROTEINS
  • SIGNALING

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