Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.
The nuclear receptor PPARalpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARalpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARalpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARalpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPARalpha 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 PPARalpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPARalpha ligand-binding domain and coactivator peptide motifs was comparable to PPARalpha agonists, but interactions with PPARdelta were weak and none were detected with PPARgamma. Portal vein infusion of 16:0/18:1-GPC induced PPARalpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPARalpha ligand.
Chakravarthy
Manu V
MV
Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Lodhi
Irfan J
IJ
Yin
Li
L
Malapaka
Raghu R V
RR
Xu
H Eric
HE
Turk
John
J
Semenkovich
Clay F
CF
D000818:Animals; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D010743:Phospholipids / Q000302:isolation & purification* / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
C491899:Fas protein, mouse; D008024:Ligands; D047493:PPAR alpha; D010743:Phospholipids; D019014:fas Receptor