Figure 1.
Schematic representation of bile acid synthesis pathways in humans. Bile acid synthesis from cholesterol occurs via different pathways. The classic pathway occurs in the liver and is responsible for the majority of bile acid synthesis. This pathway is initiated by the enzyme cholesterol 7α-hydroxylase (encoded by CYP7A1) and results in the formation of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA). Key enzymes for the formation of CA or CDCA are sterol 12α-hydroxylase (CYP8B1) and sterol-27 hydroxylase (CYP27A1), respectively. In rodents, the primary bile acids formed are CA and muricholic acid (MCA). The primary bile acids are conjugated to the amino acids glycine (G, mainly in humans) or taurine (T, mainly in rodents) forming conjugated bile acids and bile salts. The formation of secondary bile acids occurs in the intestine under the control of gut flora and when returned to the liver these secondary bile acids can also be conjugated to glycine and taurine. The alternative pathway of bile acid synthesis also occurs in other tissues besides the liver. This pathway is initiated by CYP27A1 and also involves CYP7B1. After several metabolic steps CDCA is formed. The last pathway occurs in the brain and is believed to be important for neuronal cholesterol clearance. Cholesterol is converted to 24(S)-hydroxycholesterol by CYP46A1 and subsequently exits the brain and enters the bloodstream (dotted line). In the liver, bile acid synthesis continues involving CYP39A1 resulting in CDCA after several steps.