Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.

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.

authors

Lee CH,Kang K,Mehl IR,Nofsinger R,Alaynick WA,Chong LW,Rosenfeld JM,Evans RM

doi

10.1073/pnas.0510815103

keywords:

subject

Has Abstract

pub_date

2006-02-14 00:00:00

pages

2434-9

issue

7

eissn

0027-8424

issn

1091-6490

pii

0510815103

journal_volume

103

pub_type

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