Regulation of Bile Acid Biosynthesis

Abstract

Abstract: An elevated concentration of low density lipoprotein (LDL) cholesterol is an independent risk factor for cardiovascular disease. The only quantitatively significant way by which cholesterol is removed from the body is via the bile, either directly or after conversion to bile acids. Therapeutic modalities which increase bile acid biosynthesis, e.g. bile acid-binding resins, have been shown to reduce plasma LDL levels and the risk of coronary heart disease. Their effects, however, are limited and patients' acceptibility is poor. This warrants the search for more potent drugs and new ways to enhance bile acid synthesis. In this review the various pathways along which bile acids are formed will be discussed with emphasis on the regulation of cholesterol 7o:-hydroxylase, the major rate­ limiting step in bile acid formation, as a target to increase bile acid synthesis. In the past 5 years our understanding of the transcriptional mechanism that regulates the expression of this gene has rapidly expanded. In view of the increasing evidence for the substantial contribution of the alternative or 27- hydroxylase route to bile acid synthesis, the current knowledge on sterol 27-hydroxylase, the first enzyme in this pathway and a potentially new target, is reviewed. Several companies are involved in developing new bile acid sequestrants and other inhibitors of intestinal bile acid absorption to remove cholesterol from the body. This review article presents recent developments in this field as appeared in the patent literature during past the years.