BILE-ACID SYNTHESIS FROM CHOLESTEROL - REGULATORY AND AUXILIARY PATHWAYS

Bile acid synthesis from cholesterol can occur via two pathways, one i nitiated by sterol 27-hydroxylase activity or one initiated by that of cholesterol 7 alpha-hydroxylase. In contrast to cholesterol 7 alpha-h ydroxylase, which is found in the liver, sterol 27-hydroxylase is a wi dely distributed mitochondrial enzyme with high activity in vascular e ndothelial cells. Although both pathways lead to the production of che nodeoxycholic and cholic acids, the key step, 7 alpha-hydroxylation, i s governed by two different enzymes. Both 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid, the metabolites of cholesterol occur ring via sterol 27-hydroxylase activity, normally circulate in plasma. After their uptake by the liver they are metabolized mostly to chenod eoxycholic acid, which downregulates the activity of cholesterol 7 alp ha-hydroxylase, the rate-limiting step for the production of bile acid s in the liver. Because of this relationship and also in view of the a ccelerated 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-hy droxylation is modulated by genetic, hormonal, and probably dietary fa ctors, and becomes most prominent with the interruption of the enteroh epatic circulation of bile acids.-Javitt, N. B. Bile acid synthesis fr om cholesterol: regulatory and auxiliary pathways.