Enzymes in the Conversion of Cholesterol into Bile Acids

Abstract

This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

“…Among them, CYP27A1 and CYP2R1 are considered the most promising candidates for vitamin D 25-hydroxylation. CYP27A1, also known as the sterol 27-hydroxylase, is a key enzyme in bile acid formation (6,7). Recombinant CYP27A1 is able to catalyze multiple oxidation reactions with broad substrate specificity in vitro (8)(9)(10)(11)(12)(13)(14).…”

Influence of Experimental Chronic Social Stress on Bile Acids Content in the Bile of Male Rats

“…Причому у стресованих тварин вміст глікокон'югатів у всіх 6 зібраних впродовж гострого досліду менший, ніж у контрольних пробах. Таким чином, оскільки концентрація глікохолатів виявляється нижчою від контр- [7,10,23]. Найбільш значною відмінністю у жовчно-кислотному спектрі жовчі самців щурів при хронічному соціальному стресі стала поява у їх печінковому секреті літохолевої кислоти та її таурокон'югованої форми (див.…”

Epigenetic regulation of oxysterol formation

“…CYP7A1 encodes the cholesterol 7α-hydroxylase enzyme which is the initial and rate limiting step in the classical pathway for bile acid formation [2]. It is highly expressed in the hepatocytes of the liver but virtually absent form all other tissues [5].…”

“…CYP27A1 encodes the enzyme sterol 27-hydroxylase which is the initial step in the alternate (or acidic) pathway for bile acid formation [2]. It is widely expressed enzyme and is found in many different cells and tissues.…”

“…Oxysterols may be formed by two processes -nonenzymatic mechanisms mediated by reactive chemical species such as reactive oxygen species (ROS) [1] and enzymatic processes [2,3]. With one exception (24S,25-epoxycholesterol) all oxysterols are formed either directly from cholesterol, or from oxysterols derived from cholesterol [4].…”