FXR

From LipidomicsWiki

FARNESOID X RECEPTOR, THE BILE ACID SENSOR
Although supraphysiological concentrations of the cholesterol precursor farnesol can weakly activate FXR, the relevant biological ligands for FXR are now known to be certain bile acids, including chenodeoxycholic acid, cholic acid, and their respective conjugated metabolites (Russell 1999). FXR is highly expressed in the enterohepatic system, where it acts as a bile acid sensor that protects the body from elevated bile acid concentrations. A number of in vitro and in vivo studies using mouse models have elucidated the FXR gene regulatory cascade (Goodwin et al. 2000; Lu et al. 2000; Sinal et al. 2000). FXR activation results in the up-regulation of ABCB11 (also known as the bile salt efflux pump, BSEP), a bile acid transporter that increases the flow and secretion of these detergent-like molecules into bile, where they are required for the solubilization and absorption of lipids and fat-soluble vitamins in the intestine (Sinal et al. 2000; Ananthanarayanan 2001). In the enterocytes of the ileum, bile acids are efficiently reclaimed for return to the liver. In these ileal enterocytes, bile acids induce the expression of a cytosolic binding protein called IBABP (ileal bile acid binding protein), another FXR target gene that has been proposed to buffer intracellular bile acids and promote their translocation into the portal circulation (Makishima 1999). In the liver, bile acid activation of FXR represses transcription of the key CYP genes involved in bile acid synthesis (Fig. 53). Much of this feedback repression is due to FXR-mediated up-regulation of SHP (small heterodimer partner), an atypical orphan nuclear receptor that functions as a transcriptional repressor (Goodwin et al. 2000; Lu et al. 2000). SHP interacts with and represses LRH-1, an orphan nuclear receptor that is required for liver-specific expression of CYP7A1 and sterol 12 -hydroxylase (CYP8B), the enzyme responsible for the synthesis of trihydroxy-bile acids, such as cholic acid. Thus, FXR uses a rather unique variation on the ligand sensor cascade to maintain bile acid homeostasis.