Phosphatidylcholine and PPAR: A relevant connection in liver disease? - 21/06/10

Doi : 10.1016/j.gcb.2010.02.005

A. Lamaziere, C. Wolf ^⁎
Mass Spectrometry group, faculté de médecine UPMC-Paris6, 27, rue Chaligny, Paris 75012, France

Corresponding author.

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Summary

The nuclear receptors known as PPARs modulate metabolic and inflammatory pathways by responding to nutritional signals through ligand activation of transcription. They are targeted by drugs in use and in development for disease therapy. No endogenous PPAR⍺ ligand has been identified yet; the molecule that occupies the nuclear receptor-binding site in vivo while the receptor is actively driving transcription has been presently searched for by Chakravarthy et al. The group provides now a solid evidence that endogenous lipid synthesis generates a discrete phosphatidylcholine species, 1-palmitoyl 2-oleyl phosphatidylcholine (16:0/18:1 PC), that serves as an endogenous ligand for PPAR⍺.

“Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.” Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF. Cell. 2009; 138(3):476–88. The nuclear receptor PPAR⍺ is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPAR⍺-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPAR⍺ ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPAR⍺ isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPAR⍺ agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knock down of Cept1, required for phosphatidylcholine synthesis, suppressed PPAR⍺-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPAR⍺ ligand binding domain and coactivator peptide motifs was comparable to PPAR⍺ agonists, but interactions with PPARγ were weak and none were detected with PPARγ. Portal vein infusion of 16:0/18:1-GPC induced PPAR⍺-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPAR⍺ ligand.

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