Peroxisome Proliferator-Activated Receptor α Reduces Cholesterol Esterification in Macrophages

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Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARα 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 PPARα activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARα activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARα activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARα activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARα 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, PPARα activation blocked CE formation induced by TNF-α, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-α. In conclusion, our results identify a role for PPARα in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.