Structures of ligands that interact with FXR and/or PXR. Compounds that are agonists for FXR or PXR are shown in panels (A) and (B), respectively. The effective agonist concentration that elicits 50% of maximum activation of the respective human receptor (EC₅₀) is provided, with the exception of PCN, a selective mouse PXR ligand, where the EC₅₀ for mouse PXR is shown. Guggulsterone, a promiscuous nuclear receptor ligand that acts as both an FXR antagonist and a PXR agonist, is shown in (C). Ursodeoxycholic acid, a naturally occurring epimer of chenodeoxycholic acid that is used in the therapy of some cholestatic liver disorders, but is not thought to significantly interact with nuclear receptors, is shown for comparative purposes in (D). CDCA, chenodeoxycholic acid; PCN, pregnenolone 16α-carbonitrile.

FXR-mediated bile acid transport and metabolism in the hepatocyte. Hepatic uptake of bile acids from the circulation takes place at the sinusoidal (basolateral) membrane of the hepatocyte and is mediated by NTCP and several members of the OATP family. Within the hepatocyte, bile acids can be converted to cholesterol or eliminated via bile. In addition, cholesterol can be converted to bile acids by CYP7A1. Bile acids can activate FXR which in turn induces the expression of the bile acid transporter ABCB11 (BSEP) and the phospholipid transporter ABCB4 (MDR2/3). Bile acid secretion is also stimulated by the phospholipid flippase ATP8B1. Loss of ATP8B1 results in reduced activity and nuclear translocation of FXR which is caused by impaired protein kinase C zeta (PKCzeta)-mediated phosphorylation of FXR. Negative feedback on bile acid metabolism and secretion is mediated by SHP, which is induced by FXR and inhibits the action of several NRs including LXR, HNF4α and LRH-1. Via an alternative pathway, cholesterol is converted to oxysterols that can activate LXR which in turn induces the expression of the sterol transporters ABCG5/8 at the canalicular membrane. During cholestasis bile acids can also be excreted back into the circulation via the sinusoidal ABC-transporters MRP3 and 4. MRP4 in turn is repressed by FXR through competition for binding to an overlapping binding site with CAR.

Regulation of enterohepatic circulation of bile acids by FXR. FXR regulates the enterohepatic circulation of bile acids in the hepatocyte and enterocyte. After a meal, bile is released from the gallbladder into the duodenum. Bile acid re-uptake in the ileum is mediated by ASBT in the brush border membrane. In the enterocyte, FXR induces the expression of OSTα/β, which mediate bile acid transport from the enterocyte into the portal circulation to hepatocytes where they are taken up via NTCP. In the hepatocyte, FXR induces the expression of BSEP, which mediates bile acid excretion into bile. Negative feedback on the enterohepatic circulation of bile acid is mediated by SHP, which is induced by FXR and inhibits CYP7A1 and NTCP in the hepatocyte, and ASBT in the enterocyte. Alternatively, in the endocrine pathway, FXR in the enterocyte induces the expression and secretion of FGF15/19, which binds in the liver to the FGFR4/βKlotho receptor complex and in turn activates JNK and ERK signaling pathways. Activation of the JNK and ERK pathways results in repression of CYP7A1 and stabilization of SHP by inhibition of its proteasomal degradation, respectively.

PXR-mediated bile acid transport and metabolism in the hepatocyte. PXR can mitigate the harmful effects of toxic bile acids (BA) such as LCA by activation of hepatic detoxification pathways. Activation of PXR induces the uptake of xeno- and endobiotics (phase 0), their modification by members of the cytochrome P450 subfamily (phase I), conjugation by glutathione S-transferases (GSTs), UDP-glucuronosyl-transferases (UGTs) and sulfotransferases (SULTs) (phase II) and elimination (phase III) by MRP2 (excretion of bilirubin and some bile acids), and the multidrug transporter MDR1 (excretion of a wide variety of xenobiotics and endobiotics). PXR can be directly activated by certain bile acids or indirectly via transcriptional regulation by FXR. Negative feedback on bile acid metabolism is mediated by inhibition of CYP7A1. During cholestasis bile acids can also be excreted back into the circulation via the sinusoidal ABC-transporters MRP3 and 4.