Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha

Excessive cholesterol is eliminated from extrahepatic cells by reverse chol esterol transport, a process by which neutral sterols are transferred to ex tracellular acceptor lipoproteins for further transport to the liver. Anoth er process independent of lipoproteins involves excretion of 3 beta -hydrox y-5-cholesten-25(R)-26-carboxylic (cholestenoic) acid, a metabolite of 27-h ydroxycholesterol. Physiological concentrations of cholestenoic acid activa ted the nuclear receptor liver X receptor alpha (LXR alpha; NR1H3), but not other oxysterol receptors. As a ligand, cholestenoic acid modulated intera ction of LXR alpha with the nuclear receptor coactivator Grip-1. Cholesteno ic acid, therefore, may function as a signaling molecule for regulation of lipid metabolism via LXR alpha.