Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.
Cell
; 138(3): 476-88, 2009 Aug 07.
Article
em En
| MEDLINE
| ID: mdl-19646743
ABSTRACT
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 (160/181-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPARalpha-dependent gene expression. Interaction of 160/181-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 160/181-GPC induced PPARalpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 160/181-GPC is a physiologically relevant endogenous PPARalpha ligand.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfolipídeos
/
PPAR alfa
/
Fígado
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article