Bile acid synthesis from cholesterol: regulatory and auxiliary pathways

Abstract

Bile acid synthesis from cholesterol can occur via two pathways, one initiated by sterol 27-hydroxylase activity or one initiated by that of cholesterol 7 alpha-hydroxylase. In contrast to cholesterol 7 alpha-hydroxylase, which is found in the liver, sterol 27-hydroxylase is a widely distributed mitochondrial enzyme with high activity in vascular endothelial cells. Although both pathways lead to the production of chenodeoxycholic and cholic acids, the key step, 7 alpha-hydroxylation, is governed by two different enzymes. Both 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid, the metabolites of cholesterol occurring via sterol 27-hydroxylase activity, normally circulate in plasma. After their uptake by the liver they are metabolized mostly to chenodeoxycholic acid, which down-regulates the activity of cholesterol 7 alpha-hydroxylase, the rate-limiting step for the production of bile acids in the liver. Because of this relationship and also in view of the accelerated atherosclerosis and cholesterol deposition in tissues that occur as a consequence of genetically determined sterol 27-hydroxylase deficiency and of the potent biologic effect of 27-hydroxycholesterol in cell culture, it is proposed that this metabolic pathway serves a regulatory function. The pathway beginning with cholesterol 7 alpha-hydroxylation is modulated by genetic, hormonal, and probably dietary factors, and becomes most prominent with the interruption of the enterohepatic circulation of bile acids.