Nuclear receptors in bile acid metabolism

Abstract

Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease.

Figure 1

Roles of FXR, PXR, VDR, and CAR in regulation of drug and bile acid metabolism. Bile acids are endogenous ligands of FXR, PXR, and VDR. Bile acids also activate CAR by an indirect mechanism. These four bile-acid–activated nuclear receptors play a critical role in the regulation of phase I hydroxylation (oxidation), phase II conjugation, and phase III transport in both drug and bile acid metabolism and coordinately regulate lipid, glucose, and energy metabolism and inflammation. Bile acid metabolism plays a key role in maintaining metabolic homeostasis and preventing NAFLD, diabetes, and obesity.

Figure 2

Bile acid synthesis, conjugation, and biotransformation. Bile acid synthesis in the liver converts cholesterol to bile acids through the classic and alternative pathways. (A) Bile acid synthesis. The classic pathway involves 17 enzymes located in the endoplasmic reticulum, cytosol, mitochondria, and peroxisomes. Four CYP monooxygenases (CYP7A1, CYP8B1, CYP27A1 and CYP7B) are involved in hydroxylation reactions. In the classic pathway, a steroid nucleus undergoes hydroxylation, isomerization, and epimerization first, then oxidative cleavage of the side chain by CYP27A1, and cleavage of the 3-C side chain by peroxisomal β oxidation. CYP7A1 is the first and rate-limiting enzyme in the classic pathway, which synthesizes two primary bile acids (CA and CDCA) in the human liver. CYP8B1 is required for synthesis of CA. CYP27A1 catalyzes side-chain oxidation reactions. The alternative pathway is initiated by CYP27A1, followed by CYP7B1, and then further metabolized as the classic pathway to produce CDCA. (B) Conjugation of bile acids. Amidation (BACS and BAAT), sulfation (SULT2A1), and glucuronidation (UGT1A1, 2B4, and 2B7) at specific positions by specific enzymes are shown. (C) Biotransformation of bile acids. Secondary bile acids CDCA and LCA can be converted to more hydrophilic bile acids in the hepatocytes and intestine. Hydroxylation (by human CYP3A4 or mouse Cyp3a11), epimerization, and dehydroxylation interconverts CDCA to UDCA to LCA as well as other bile acids.

Figure 3

Enterohepatic circulation of bile acids. Bile acids are synthesized from cholesterol in hepatocytes. Bile acids are secreted into the gallbladder by BSEP and MRP2. Phospholipids are transported by MDR2, and cholesterol is transported by ABCG5/G8 transporters into bile. In the gallbladder, bile acids, phospholipids, and cholesterol form mixed micelles to solubilize cholesterol and reduce bile acid toxicity. After meal intake, the gallbladder releases bile into the small intestine, where bile acids facilitate the absorption of dietary lipids and vitamins. At the terminal ileum, most of the bile acids are reabsorbed by ASBT into the enterocytes and are secreted into the portal circulation by the basolateral bile acid transporters, Ostα/Ostβ. At the basolateral membrane of the hepatocytes, bile acids are taken up by the NTCP transporter for resecretion into the gallbladder, whereas Ostα/Ostβ and MRPs are responsible for basolateral bile acid efflux.