Bile acid-activated receptors in the treatment of dyslipidemia and related disorders.

Dyslipidemia is a metabolic disorder that constitutes a major risk factor for cardiovascular diseases and stroke and is often associated with diabetes mellitus and atherosclerosis. In recent years a number of ligand-activated receptors have been found to exert a role in integrating essential steps of lipid and glucose metabolism. Bile acid-activated receptors are a defined subset of nuclear and G-protein coupled receptors mainly expressed in entero-hepatic tissues for which bile acids function as signaling molecules. Primary bile acids (chenodeoxycholic acid and cholic acid) are physiological ligands/activators of farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR) and constitutive androstane receptor (CAR), while litocholic acid is a ligand for the Vitamin D receptor (VDR) and the G-protein coupled receptor TGR5. Despite FXR demonstrates a high selectivity for bile acids, PXR and CAR are relatively promiscuous receptors integrating lipid homeostasis with xenobiotic metabolism. FXR, PXR, CAR and TGR exert synergistic activities in regulating lipid and glucose homeostasis and energy expenditure and liver and peripheral insulin sensitivity. Ligands for these receptors hold promise in the treatment of dyslipidemic conditions as revealed by results of a number of preclinical models but carry a defined risk for potential side effects. Copyright 2009 Elsevier Ltd. All rights reserved.