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The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor α (PPARα), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARα and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARα ligands in human macrophages. Furthermore, PPARα activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPARα activators. These observations identify a novel regulatory role for PPARα in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport.

The metabolic syndrome is defined as the clustering of cardiovascular risk factors, such as glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances and hypertension. Activators of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors pre-disposing to atherosclerosis. Fibrates are hypolipidemic drugs operating through activation of PPARα, whereas glitazones are insulin sensitizers activating PPARγ. In addition, these drugs exert pleiotropic and anti-inflammatory actions. This review will focus on the different effects of fibrates and glitazones, as measured by biomarker modulation, on the development of atherosclerosis and cardiovascular disease.

The metabolic syndrome is defined as the clustering of cardiovascular risk factors, such as glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances and hypertension. Activators of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors pre-disposing to atherosclerosis. Fibrates are hypolipidemic drugs operating through activation of PPARα, whereas glitazones are insulin sensitizers activating PPARγ. In addition, these drugs exert pleiotropic and anti-inflammatory actions. This review will focus on the different effects of fibrates and glitazones, as measured by biomarker modulation, on the development of atherosclerosis and cardiovascular disease.