Xol INXS: role of the liver X and the farnesol X receptors

Cholesterol and bile acid metabolism is tightly controlled by nuclear recep tors. The liver X receptor, an oxysterol-activated nuclear receptor, limits cholesterol accumulation in the body both by stimulating reverse cholester ol transport and by inhibiting intestinal cholesterol absorption. The liver X receptor stimulates the adenosine triphosphate binding cassette transpor ter (types 1 and 8)-mediated cholesterol efflux from peripheral tissues to apolipoprotein Al and the expression of the cholesterol ester transfer prot ein, hence facilitating cholesterol transfer to the liver. In the liver, th e liver X receptor alpha induces the cholesterol 7 alpha -hydroxylase (CYP7 A1) gene, which controls the rate-limiting step in bile acid synthesis, the major cholesterol excretion pathway. The liver X receptor also limits chol esterol entry in the body by promoting cholesterol efflux from enterocytes into the intestinal lumen, again via an adenosine triphosphate binding cass ette transporter type-mediated process. Whereas the liver X receptor is a m aster controller of cholesterol metabolism, the farnesol X receptor, a bile acid-activated receptor, coordinates bile acid homeostasis. Bile acids fac ilitate the solubilization of dietary lipids and their subsequent absorptio n. Bile acids enter the enterocyte through the ileal bile acid transporter and activate the farnesol X receptor, which upregulates the ileal bile acid binding protein, a carrier protein facilitating their re-uptake by the gut . Bile acids are then delivered into the portal blood and taken up in the h epatocytes by the sodium taurocholate co-transporting polypeptide. Inside t he hepatocytes, activated farnesol X receptor will decrease further bile ac id uptake by reducing the levels of sodium taurocholate co-transporting pol ypeptide, and stimulating the export of bile acid by increasing the express ion of the bile salt export pump. Furthermore, the farnesol X receptor indu ces the small heterodimer partner, an atypical nuclear receptor, which atte nuates bile acid synthesis by inhibiting the action of the orphan nuclear r eceptor, liver receptor homolog-1, which is a competence factor for CYP7A1 transcription. The farnesol X receptor hence stimulates bile acid re-uptake and controls bile acid production through a regulatory circuit involving b oth a nuclear receptor regulatory cascade and a number of specific transpor ter proteins. Curr Opin Lipidol 12:113-120. (C) 2001 Lippincott Williams & Wilkins.