Bile acid synthesis, regulation

Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72 137-174... 

Bile Acid Synthesis Is Regulated at the 7a-Hydroxylase Step... 

Princen HMG Regulation of bile acid synthesis. Curr Pharm Design 1997 3 59. 

Reihner E, Bjorkhem I, Angelin B, Ewerth S, Einarsson K. Bile acid synthesis in humans regulation of hepatic microsomal cholesterol 7 alpha-hydroxy-... 

M. Fuchs, Bile Regulation of Hepatic Physiology 3, Regulation of Bile-acid synthesis Past Progress and Future Challenges, Am. J. Physiol. Gas-trointest. Liver Physiol., 2003, 284, 551-557. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Chiang, J.Y.L. 2004. Regulation of bile acid synthesis pathways, nuclear receptors, and... 

HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis, and is subject to complex regulatory controls. A relatively constant level of cholesterol in the body (150-200 mg/dl) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilised in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis. 

Schreiber, A.J. and Simon, F.R., Overview of clinical aspects of bile salt physiology, J. Pediatr. Gastroenterol. Nutr. 2, 337-345, 1983 Chiang, J.Y., Regulation of bile acid synthesis. Front. Biosci. 3, dll76-dll93, 1998 Cybulsky, M.I., Lichtman, A.H., Hajra, L., and liyama, K., Leukocyte adhesion molecules in atherogenesis, Clin. ChirtL Acta 286, 207-218, 1999. 

The regulation of bile acid metabolism is a major function of the liver. Alterations in bile acid metabolism are usually a reflection of liver dysfunction. Cholesterol homeostasis is in large part maintained by the conversion of cholesterol to bile acids and subsequent regulation of bile add metabolism. Bile acids themselves provide surface-active detergent molecules that facilitate both hepatic excretion of cholesterol and solubilization of lipids for intestinal absorption. Bile acid homeostasis requires normal terminal ileum function to absorb bile adds for recirculation (enterohepatic circulation). Alterations in hepatic bile acid synthesis, intracellular metabolism, excretion, intestinal absorption, or plasma extraction are reflected in derangements in bile add metabolism. 

Patients also develop cholesterol gallstones from a defect in bile acid synthesis. The defect is in the mitochondrial C27-steroid 27-hydroxylase. In these patients, the reduced formation of normal bile acids, particularly chenodeoxycholic acid, leads to the up-regulation of the rate limiting enzyme Tct-hydroxylase of the bile acid synthetic pathway (discussed later). This leads to accumulation of 7a-hydroxylated bile acid intermediates that are not normally utilized. 

Chiang JYL. Regulation of bile acid synthesis. Front Biosci 1998 3 D176-93. Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7a-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 2002 110(1) 109-17. 

An alternative mechanism for regulating bile acid synthesis is via cholesterol availability. Although cholesterol which has been newly synthesized in... 

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