ABSTRACT
Conversion of cholesterol to bile acids in the liver is the major catabolic pathway for disposal of cholesterol in mammals. Bile acids are important physiological agents, which facilitates the disposal of sterols and xenobiotics, and absorption and transport of lipid soluble vitamins and fats. Enterohepatic circulation of bile acids is very efficient and plays important physiological roles not only in secretion and distribution of nutrients but also in regulation, the rate of bile acid biosynthesis. Two major bile acid biosynthesis pathways have been established. The classical (or neutral) pathway is initiated by the rate-limiting enzyme, microsomal cholesterol 7α-hydroxylase (CYP7A1), to synthesize cholic acid (CA) and chenodeoxycholic acid (CDCA), the primary bile acids. In this pathway, microsomal sterol 12α-hydroxylase (CYP8B1) is required for the synthesis of cholic acid and mitochondrial sterol 27-hydroxylase for side-chain oxidation. The alternative pathway is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1), followed by oxysterol 7α-hydroxylase (CYP7B1) in extrahepau’c tissues. Oxysterol metabolites are then transported from peripheral tissues into hepatocytes and further conversion to CDCA. These four cytochrome P450 genes have recently been cloned and molecular mechanisms of regulation of these major regulatory genes in bile acid biosynthesis are currently under study. Several inborn errors of bile acid biosynthesis have been identified. Advances in molecular genetics of bile acid biosynthesis have led to a better understanding of the molecular basis of regulation of bile acid synthesis, the mechanisms of pathogenesis of cholestatic liver diseases, and the therapy for treatment of hypercholesterolemia and cholestatic liver diseases.
