Abstract-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. (Circ Res. 2005;97:682-689.)Key Words: nuclear receptor Ⅲ gene regulation Ⅲ metabolism Ⅲ atherosclerosis D uring the initial stages of atherogenesis, monocytes migrate into the subendothelial space of blood vessels and differentiate into macrophages. The uptake of excessive amounts of lipoprotein-derived lipids converts them into foam cells. 1 After uptake, modified low-density lipoprotein (LDL)-derived cholesteryl esters (CEs) are hydrolyzed in late endosomes/lysosomes to free cholesterol, which then traffics to and integrates into the plasma membrane. 1 Excess membrane cholesterol is transported back to the endoplasmic reticulum, where it is re-esterified with fatty acids (FAs) by acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) and stored in lipid droplets. 2 However, not all LDL-derived cholesterol traffics to the plasma membrane because a fraction is directly transported to the endoplasmic reticulum for esterification. The amount of lipid accumulation in macrophages reflects the balance between the rate of cholesterol accumulation/uptake and its removal via the reverse cholesterol transport pathway. 3 Availability of cholesterol in the plasma membrane is a crucial step for cholesterol efflux.The molecular mechanisms responsible for regulating intracellular cholesterol transport and homeostasis are subject of intense investigation, and much of the knowledge has been gained from studies on the Niemann-Pick C (NPC) disease, a fatal recessive disorder caused by mutations in either the NPC1 or NPC2 genes. 4 Mutations in NPC1 cause the majori...
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