Title : Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage - Lee_2006_Proc.Natl.Acad.Sci.U.S.A_103_2434 |
Author(s) : Lee CH , Kang K , Mehl IR , Nofsinger R , Alaynick WA , Chong LW , Rosenfeld JM , Evans RM |
Ref : Proc Natl Acad Sci U S A , 103 :2434 , 2006 |
Abstract :
Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease. |
PubMedSearch : Lee_2006_Proc.Natl.Acad.Sci.U.S.A_103_2434 |
PubMedID: 16467150 |
Lee CH, Kang K, Mehl IR, Nofsinger R, Alaynick WA, Chong LW, Rosenfeld JM, Evans RM (2006)
Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage
Proc Natl Acad Sci U S A
103 :2434
Lee CH, Kang K, Mehl IR, Nofsinger R, Alaynick WA, Chong LW, Rosenfeld JM, Evans RM (2006)
Proc Natl Acad Sci U S A
103 :2434