Xol INXS: role of the liver X and the farnesol X receptors
Cholesterol and bile acid metabolism is tightly controlled by nuclear receptors. The liver X receptor, an oxysterol-activated nuclear receptor, limits cholesterol accumulation in the body both by stimulating reverse cholesterol transport and by inhibiting intestinal cholesterol absorption. The liver X receptor stimulates the adenosine triphosphate binding cassette transporter (types 1 and 8)-mediated cholesterol efflux from peripheral tissues to apolipoprotein AI and the expression of the cholesterol ester transfer protein, hence facilitating cholesterol transfer to the liver. In the liver, the liver X receptor alpha induces the cholesterol 7alpha-hydroxylase (CYP7A1) gene, which controls the rate-limiting step in bile acid synthesis, the major cholesterol excretion pathway. The liver X receptor also limits cholesterol entry in the body by promoting cholesterol efflux from enterocytes into the intestinal lumen, again via an adenosine triphosphate binding cassette transporter type-mediated process. Whereas the liver X receptor is a master controller of cholesterol metabolism, the farnesol X receptor, a bile acid-activated receptor, coordinates bile acid homeostasis. Bile acids facilitate the solubilization of dietary lipids and their subsequent absorption. 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 hepatocytes by the sodium taurocholate co-transporting polypeptide. Inside the hepatocytes, activated farnesol X receptor will decrease further bile acid uptake by reducing the levels of sodium taurocholate co-transporting polypeptide, and stimulating the export of bile acid by increasing the expression of the bile salt export pump. Furthermore, the farnesol X receptor induces the small heterodimer partner, an atypical nuclear receptor, which attenuates bile acid synthesis by inhibiting the action of the orphan nuclear receptor, 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 both a nuclear receptor regulatory cascade and a number of specific transporter proteins.