ABSTRACT
Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of inflammation-related diseases, such as atherosclerosis. This review focuses on recent advances on the role of the peroxisome proliferator-activated receptor transcription factor family in the modulation of lipid homeostasis and the inflammatory response in macrophages and the potential participation of these actions in the modulation of metabolic and cardiovascular disease.
Subject(s)
Atherosclerosis , Cardiovascular Diseases/drug therapy , Cholesterol/metabolism , Hypolipidemic Agents/therapeutic use , Macrophages/drug effects , Peroxisome Proliferator-Activated Receptors , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Clinical Trials as Topic , Fenofibrate/adverse effects , Fenofibrate/therapeutic use , Gemfibrozil/adverse effects , Gemfibrozil/therapeutic use , Humans , Macrophages/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/drug effects , Peroxisome Proliferator-Activated Receptors/physiologyABSTRACT
Liver X receptors (LXRs) are nuclear receptors that regulate macrophage cholesterol efflux by inducing ATP-binding cassette transporter A1 (ABCA1) and ABCG1/ABCG4 gene expression. The Niemann-Pick C (NPC) proteins NPC1 and NPC2 are located in the late endosome, where they control cholesterol trafficking to the plasma membrane. The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant governing its availability for efflux to extracellular acceptors. Here we investigated the influence of LXR activation on intracellular cholesterol trafficking in primary human macrophages. Synthetic LXR activators increase the amount of free cholesterol in the plasma membrane by inducing NPC1 and NPC2 gene expression. Moreover, ABCA1-dependent cholesterol efflux induced by LXR activators was drastically decreased in the presence of progesterone, which blocks postlysosomal cholesterol trafficking, and reduced when NPC1 and NPC2 mRNA expression was depleted using small interfering RNA. The stimulation of cholesterol mobilization to the plasma membrane by LXRs led to a decrease in cholesteryl ester formation and Acyl-coenzyme A cholesterol acyltransferase-1 activity. These data indicate that LXR activation enhances cholesterol trafficking to the plasma membrane, where it becomes available for efflux, at the expense of esterification, thus contributing to the overall effects of LXR agonists in the control of macrophage cholesterol homeostasis.
