Fig. 1

Metabolism and circulation of bile acids in periphery and brain. The catabolism of cholesterol to primary bile acids (BA) in liver by two pathways, involving the critical enzymes cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) in the classical pathway to form cholic acid (CA), and sterol 27-Hydroxylase (CYP27A1) and oxysterol 7α-hydroxylase (CYP7B1) in the alternative pathway to synthesize chenodeoxy cholic acid (CDCA). The neural cholesterol clearance pathway is initiated by CYP46A1 to form 24(S)-hydroxycholesterol (24-OHC) from cholesterol. 24-OHC subsequently crosses the BBB, and is metabolized by CYP39A1 in the liver to synthesize CDCA. The brain 27-OHC converted by CYP27A1 might also cross the BBB and is metabolized by CYP7B1 in the liver. The primary BA are converted to conjugated forms with glycine or taurine. Then, primary BA are further converted to the secondary BA metabolized by the gut microbes. After re-absorption through passive diffusion or bile acid transporters, about 95% of BA are reabsorbed in the ileum and returns to enterohepatic circulation. A small amount of BA in the systemic circulation can be taken up into the brain by passive diffusion or by active transport through the blood brain barrier (BBB).