Figure 1. Regulation of bile acid and xenobiotic metabolism-clearance in rodents via FXR, PXR and CAR. BAs are synthesized in the liver from cholesterol and secreted into the gallbladder after conjugation with glycine or taurine. All these steps are regulated by FXR, which can repress Cyp7a1 expression while inducing the expression of BACS and BAAT for BA conjugation, and Bsep, Mrp2 and Mrd2 for bile formation. Before BAs are concentrated in the gallbladder, a small amount of BAs is passively (unconjugated) or actively (conjugated) reabsorbed from cholangiocytes. In the latter case, the canalicular membrane transporter Asbt is responsible for the uptake of conjugated BAs that are secreted into the periductal capillary plexus via the basolateral transporters Mrp3, Mrp2, Ost-alpha/beta, to be return to the liver. The majority of BAs concentrate in the gallbladder and after postprandial stimulus are delivered into the small intestine to allow the absorption of lipophilic nutrients. After reaching the distal ileum, most conjugated BAs are actively reabsorbed by the canalicular transporter Asbt, while some unconjugated BAs are passively reabsorbed from the distal ileum and the proximal colon where secondary BAs (LCA, DCA) are produced by anaerobic bacteria. Only a very small amount of BAs is lost with feces. After being taken-up by Asbt, BAs induce FGF15 expression in the ileum via FXR, to communicate to the liver the need to stop BA synthesis by down-regulating Cyp7a1 expression. At the same time, BAs are shuttled to the basolateral membrane of the ileal enterocyte by the cytosolic transporter Ibabp. Afterward, BAs are secreted in the portal blood via Mrp3 and Ost-alpha /beta transporters to travel back to the liver and complete the enterohepatic circulation. After being taken-up from the liver by Ntcp, BAs activate FXR and repress their own synthesis by down-regulating Cyp7a1 expression via SHP. Also, PXR can repress Cyp7a1 expression when BAs accumulate in the liver to toxic levels. During cholestasis, several adaptive mechanisms are coming into play. PXR and CAR help FXR to induce phase I (Cyp3a11) and phase II (Sult2a1) BA metabolism, besides to stimulate BA secretion via Mrp2. Moreover, when canalicular secretion is impaired, FXR, PXR, and CAR can also induce an alternative basolateral secretion (through Ost-alpha /beta, Mrp3 and Mrp2) that diverts BAs in the blood stream for final elimination of hydroxylated and sulfonated BAs with urines. FXR protects also the intestine from the toxic effects of accumulating intracellular BAs by repressing Asbt expression while inducing that of Ibabp and Ost-alpha/beta to spill over BAs from the enterocyte. During cholestasis, by inducing Oatp1a4 expression, PXR allows the liver to conserve a minimal ability to metabolize BAs and xenobiotics when Ntcp expression is repressed by FXR via SHP. Orally dosed drugs are absorbed by the intestine where they can activate PXR or CAR to induce their own metabolism via Cyp3a11 and further secretion into the gut lumen via Mdr1 as hydroxylated products ready for fecal elimination. Those drugs that can reach the liver are withdrawn by Oatp1a4 and activate hepatic PXR and CAR, which in turn induce both phase I (Cyp3a11) and phase II (Sult2a1, Ugt1a6) drug metabolism, as well as phase III hepatic clearance via Mdr1 for the secretion of hydroxylated, sulfonated and glucuronidated drugs into the bile for fecal elimination.