Figure 1.

(A) Bile acids are synthesized in the liver from cholesterol by two metabolic pathways known as the neutral (or classical) and the acidic (alternative) pathways. In the classical pathway, cholesterol is metabolized to 7α-hydroxycholesterol by cholesterol 7α-hydroxylase (CYP7A1) and then to cholic acid (CA) by sterol 12α-hydroxylase (CYP8A1) or to chenodeoxycholic acid (CDCA) by mitochondrial sterol 27-hydroxylase (CYP27A1). On the other hand, in the acidic pathway, CYP27A1 converts cholesterol into 27-hydroxycholesterol which is then metabolized by 25-hydroxycholesterol 7α-hydroxylase (CYP7B1) into CDCA. The two primary bile acids, CA and CDCA, are then secreted into bile ducts and transported to the intestine where they are respectively converted by microbial bile salt hydrolases, an enzyme expressed predominantly by Bacteroides, Clostridium, Lactobacillus, and Bifidobacteria, and by a bacterial 7α-dehydroxylase, mainly expressed by Clostridium and Eubacterium, in deoxycholic acid (DCA) and in lithocholic acid (LCA) called secondary bile acids. (B) Bile acid metabolism in liver cells and adaptive changes activated in cholestasis by Farnesoid-X-Receptor (FXR). Na⁺-taurocholate cotransporting polypeptide (NTCP) is a basolateral transporter that allow uptake of bile acids (CA, CDCA, DCA, and LCA) by hepatocytes. Primary and secondary bile acids are then amidated with glycine or taurine by bile acid-CoA:amino acid N-acyltransferase (BAAT) or bile acyl CoA synthetase and then secreted again into bile ducts through the apical transporters bile salt export pump (BSEP), multidrug resistance-associated protein 2, and multidrug resistance protein 2 and 3. Alternatively, an outflow occurs via the basolateral transporters MRP4 and organic solute transporter α/β (OST α/β). The main regulatory mechanism in this pathway is contributed by the FXR which, once activated by its endogenous ligand CDCA, represses the transcription of CYP7A1 through the small heterodimer partner (SHP), thus inhibiting the classical pathway of bile acids synthesis. Furthermore, the activation of FXR up-regulates the transporters OSTα/β, MRP1, and BSEP, and down-regulates NTCP, promoting the bile acids export. (C,D) Activation of intestinal FXR on enterocytes causes the release of fibroblasts growth factor (FGF)-15 (FGF-19 in humans) which binds to the FGF receptor 4 (FGF-R4) on hepatocytes and inhibits CYP7A1 transcription. Further on, in the intestine secondary bile acids cause a G-protein bile acid receptor 1-dependent release of glucagon-like peptide 1 (GLP-1) from intestinal “L” endocrine cells. GLP-1, in its turn, regulates insulin secretion by pancreatic β-cells.