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.