Fig. 2. Bile acid synthesis, enterohepatic circulation of bile acids, and bile acid transport. In human hepatocytes, cholesterol 7α-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classic pathway of bile acid synthesis in which cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized from cholesterol. Sterol 12α-hydroxylase (CYP8B1) is required for synthesis of CA, and without this enzyme CDCA is synthesized. The alternative pathway is initiated by sterol 27-hydroxylase (CYP27A1), which catalyzes steroid side-chain oxidation, followed by oxysterol 7α-hydroxylase (CYP7B1), which synthesizes the oxidized sterols that form CA and CDCA in hepatocytes. CYP7A1 is liver-specific, while CYP27A1 and CYP7B1 are expressed in extrahepatic tissues and macrophages. Bile acids are conjugated to the amino acids taurine (T) or glycine (G) for secretion into bile via bile salt export pump (BSEP). Bile acids are reabsorbed in the ileum via apical sodium-dependent bile acid transporter (ASBT) in enterocytes, where gut bacterial bile salt hydrolase (BSH) de-conjugates bile acids and 7α-dehydroxylase removes a hydroxyl group to form the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA) from CA and CDCA, respectively. Bile acids are effluxed to portal blood via organic solute transporter α and β (OSTα/OSTβ) dimers and are transported to hepatocytes via Na²⁺-dependent taurocholate co-transporting peptide (NTCP) where they inhibit bile acid synthesis. Bile acids activate hepatic farnesoid X receptor (FXR) to induce small heterodimer partner (SHP), which inhibits CYP7A1 and CYP8B1 gene transcription. In enterocytes, bile acid activation of FXR induces fibroblast growth factor 19 (FGF19). FGF19 is transported to hepatocytes to activate FGF receptor 4 (FGFR4)/β-Klotho complex, which activates EKR1/2 signaling to inhibit CYP7A1 gene transcription. Bile acids activate Takeda G protein-coupled receptor 5 (TGR5) in intestinal L-cells, leading to secretion of glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from β-cells. In adipose tissue, activation of TGR5 stimulates cAMP/cAMP response element binding protein (CREBP) to induce thyroid hormone deiodinase type 2 (DIO2), which converts thyroxine (T4) to triiodothyronine (T3) and stimulates energy metabolism. ERK1/2, extracellular regulated kinase 1 and 2; PPARα, peroxisome proliferator-activated receptor α; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid.