REGULATION OF BILE ACID SYNTHESIS 

John Y. L. Chiang

Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, P. O. Box 95, Rootstown, OH 44272

Received 1/22/98 Accepted 2/2/98

2. INTRODUCTION

Conversion of cholesterol to bile acids in the liver is the most significant pathway for the elimination of cholesterol from the body. Bile acids are important physiological detergents which induce bile flow and biliary lipid secretion, facilitate the absorption of dietary fat, cholesterol, and lipid-soluble vitamins in the small intestine, and secretion of cholesterol and other compounds into feces. Bile acids are quantitatively reabsorbed in the ileum by active transport systems, and are transported back to the liver via the portal venous circulation (1). In the liver, bile acids are taken up by Na⁺-taurocholate cotransporter and Na+-independent organic anion transporting polypeptide located in the sinusoidal membrane (basolateral), shuttled vectorially by bile acid binding proteins across the hepatocyte to the canalicular surface, and secreted into the bile canalicular (apical) by canalicular multiorganic anion

transporter and ATP-dependent bile salt transporter. This enterohepatic circulation of bile acids is remarkably efficient, with only 5% bile acids lost in feces which is compensated for by biosynthesis from cholesterol. This feedback mechanism not only regulates bile acid synthesis and bile flow, but also is important in regulating cholesterol synthesis by inhibiting the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and hepatic uptake of low density lipoprotein (LDL) cholesterol by LDL receptor. Excess cholesterol in extrahepatic tissues is excreted into serum and transported by reverse cholesterol transport involving HDL to the liver. Scavenger receptor SR-BI in hepatocytes uptakes HDL-cholesterol and convert it to bile acids (2, 3). Conversion of cholesterol to bile acids accounts for the catabolism of about 50% of cholesterol in the body and bile acids are also required for the disposal of 40% of cholesterol in feces. Bile acid biosynthesis pathway thus plays an important role in maintaining cholesterol homeostasis in mammals. Bile acids are toxic biological detergents, the synthesis of which has to be tightly regulated to prevent damage of biological membranes and maintaining membrane structure and function. In past few years, knowledge on the regulation of the first and rate-limiting enzyme of the classic bile acid biosynthesis pathway, cholesterol 7alpha-hydroxylase, has been greatly advanced by molecular cloning of the gene. Much advances also has been made on the role of the alternative pathway starting with 27-hydroxylation of cholesterol. This review will focus on the molecular mechanisms of regulation of the rate-limiting enzyme, cholesterol 7alpha-hydroxylase, and other major cytochrome P450 enzymes in the pathways, sterol 27-hydroxylase, sterol 12alpha-hydroxylase and oxysterol 7alpha-hydroxylase.