Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.
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.
Lee
Chih-Hao
CH
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Kang
Kihwa
K
Mehl
Isaac R
IR
Nofsinger
Russell
R
Alaynick
William A
WA
Chong
Ling-Wa
LW
Rosenfeld
John M
JM
Evans
Ronald M
RM
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D002331:Carnitine / Q000096:biosynthesis / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008049:Lipase; D050356:Lipid Metabolism / Q000235:genetics*; D008079:Lipoproteins, VLDL / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases
D002265:Carboxylic Ester Hydrolases; D002331:Carnitine; D005227:Fatty Acids; D008049:Lipase; D008079:Lipoproteins, VLDL; D047494:PPAR delta; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases