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(Circulation Research. 2003;92:212.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Peroxisome Proliferator-Activated Receptor Reduces Cholesterol Esterification in Macrophages

G. Chinetti, S. Lestavel, J.-C. Fruchart, V. Clavey, B. Staels

From the UR 545 INSERM, Institut Pasteur de Lille and Université de Lille 2, Lille, France.

Correspondence to Giulia Chinetti, UR 545 INSERM, Institut Pasteur de Lille, 1, rue Calmette BP245, 59019 Lille, France. E-mail giulia.chinetti{at}pasteur-lille.fr

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPAR is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPAR activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPAR activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPAR activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPAR activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPAR activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPAR activation blocked CE formation induced by TNF-, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-. In conclusion, our results identify a role for PPAR in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.

Key Words: nuclear receptor • atherosclerosis • gene regulation • cholesterol homeostasis

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