Figure 2.

Bile acid synthesis pathways. In the liver, cholesterol 7α-hydroxylase (CYP7A1) initiates the classical bile acid synthesis pathway by hydroxylation of the steroid rings at 7α-C for further modifications of the steroid rings, followed by steroid side chain oxidation and cleavage, whereas sterol 27-hydroxylase (CYP27A1) initiates the alternative bile acid synthesis pathway by oxidation of the steroid side chain followed by modifications of the steroid rings and cleavage of the side chain in the classic pathway. CYP27A1 is expressed in most tissues and macrophages. Sterol 25-hydroxylase (a non-CYP450 enzyme) in the liver and steroid 24-hydroxylase (CYP46A1) in the brain also oxidize cholesterol. In the alternative pathways, a nonspecific oxysterol 7α-hydroxylase (CYP7B1) hydroxylates 27-hydroxycholesterol and 25-hydroxycholesterol, whereas a specific sterol 7α-hydroxylase (CYP39A1) hydroxylates 24-hydroxycholesterol. Only the liver has all the enzymes required for the synthesis of cholic acid (CA) and chenodeoxycholic acid (CDCA), the two primary bile acids synthesized in humans (shown on the left, see text for details). The oxidized steroid intermediates (oxysterols) produced in the extrahepatic tissues can be used for bile acid synthesis in the liver. Sterol 12α-hydroxylase (CYP8B1) is required for CA synthesis. Without 12α-hydroxylation, CDCA is synthesized. Following steroid side chain cleavage, cholyl-CoA and chenodeoxycholyl-CoA are conjugated to amino acids, either taurine or glycine. In mice, CDCA is 6α-hydroxylated to form α-muricholic acid (α-MCA) by a sterol-6α-hydroxylase (Cyp2c70) catalyzed reaction. The 7α-OH group in α-MCA is epimerized (isomerized) to a 7β-hydroxyl group to form β-MCA. The 7α-HO group in CDCA can be epimerized to 7β-HO to form ursodeoxycholic acid (UDCA), a highly soluble bile acid in humans and mice.