TY - JOUR
T1 - Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver
AU - Chakravarthy, Manu V.
AU - Lodhi, Irfan J.
AU - Yin, Li
AU - Malapaka, Raghu R.V.
AU - Xu, H. Eric
AU - Turk, John
AU - Semenkovich, Clay F.
N1 - Funding Information:
This work was supported by NIH grants DK076729, P50 HL083762, R37 DK34388, P41 RR00954, HL089301, the Clinical Nutrition Research Unit (DK56341), the Diabetes Research and Training Center (DK20579), the Jay and Betty Van Andel Foundation, and the American Diabetes Association (Junior Faculty Award 1-07-JF-12 to M.V.C. and a Mentor-Based Postdoctoral Fellowship Award).
PY - 2009/8/7
Y1 - 2009/8/7
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - PROTEINS
KW - SIGNALING
UR - https://www.scopus.com/pages/publications/68149098866
U2 - 10.1016/j.cell.2009.05.036
DO - 10.1016/j.cell.2009.05.036
M3 - Article
C2 - 19646743
AN - SCOPUS:68149098866
SN - 0092-8674
VL - 138
SP - 476
EP - 488
JO - Cell
JF - Cell
IS - 3
ER -