FXR an emerging therapeutic target for the treatment of atherosclerosis

摘要: Atherosclerosis is the leading cause of illness and death. Therapeutic strategies aimed at reducing cholesterol plasma levels have shown efficacy in either progression atherosclerotic plaques atherosclerosis-related mortality. The farnesoid-X-receptor (FXR) a member metabolic nuclear receptors (NRs) superfamily activated by bile acids. In entero-hepatic tissues, FXR functions as acid sensor regulating synthesis, detoxification excretion. liver induces expression an atypical NR, small heterodimer partner, which subsequently inhibits activity hepatocyte factor 4alpha repressing transcription 7a-hydroxylase, critical regulatory gene synthesis. intestine release fibroblast growth 15 (FGF15) (or FGF19 human), activates hepatic FGF receptor 4 (FGFR4) signalling to inhibit rodents, activation decreases synthesis lipogenesis increases lipoprotein clearance, regulates glucose homeostasis gluconeogenesis. exerts counter-regulatory effects on macrophages, vascular smooth muscle cells endothelial cells. deficiency mice results pro-atherogenetic lipoproteins profile insulin resistance but FXR(-/-) fail develop any detectable high-fat diet. Synthetic agonists protect against development aortic formation murine models characterized accelerated atherosclerosis, reduce HDL levels. Because human mouse metabolism modulated different pathways potential drawbacks ligands need addressed relevant clinical settings.