Lipid signaling in the atherogenesis context.
Normally macrophages localized in the arterial vessel wall perform the "reverse transfer" of cholesterol, which includes endocytosis of low density lipoproteins (LDL), cholesterol transfer to newly formed high density lipoprotein particles, and their following elimination by the liver. The homeostatic function of macrophages for cholesterol involves a system of lipid sensors. Oxysterol sensors LXRs, oxysterol and cholesterol sensors INSIG and SCAP acting through controlled transcription factors SREBP, as well as sensors for oxidized fatty acids and their derivatives, PPAR, are the best studied. Activation of LXR and PPAR is also accompanied by inhibition of macrophage functions related to inflammation. Accumulation of oxidized and otherwise modified LDL in the subendothelial space induced by endothelium injury, infection, or other pathogenic factors instead of stimulation of the homeostatic functions of macrophages leads to their weakening with a concurrent increase in the inflammatory potential of these cells. These shifts seem to drive the transformation of macrophages into foam cells, which form the core of sclerotic plaques. The intervention of another lipid sensor, TLR4, can trigger such a radical change in the functional activity of macrophages. The interaction of modified LDL with this signaling receptor results in inhibition of the homeostatic oxysterol signaling, induction of additional LDL transporters, and activation of the phagocytic function of macrophages. The re-establishment of cholesterol homeostasis under these circumstances can be achieved by administration of LXR and PPARgamma agonists. Therefore, it is urgent to design ligands with reduced side effects.
Smirnov
A N
AN
Lomonosov Moscow State University, Russia. smirnov__an@mail.ru
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D008077:Lipoproteins, LDL