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

Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2434-9. doi: 10.1073/pnas.0510815103. Epub 2006 Feb 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Ester Hydrolases / genetics*
  • Carboxylic Ester Hydrolases / metabolism
  • Carnitine / biosynthesis
  • Carnitine / genetics
  • Fatty Acids / metabolism*
  • Gene Deletion
  • Gene Expression Regulation*
  • Lipase
  • Lipid Metabolism / genetics*
  • Lipoproteins, VLDL / metabolism*
  • Lipoproteins, VLDL / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Oxidation-Reduction
  • PPAR delta / genetics
  • PPAR delta / metabolism*

Substances

  • Fatty Acids
  • Lipoproteins, VLDL
  • PPAR delta
  • Carboxylic Ester Hydrolases
  • Lipase
  • PNPLA2 protein, mouse
  • Carnitine