Bile-Acid Regulation

Handschin C, Podvinec M, Amherd R, Looser R, Ourlin JC, et al. 2002. Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450. J Biol Chem 277 29561-29567. 

J. Chiang, Bile acid regulation of gene expression. Roles of nuclear hormone receptors. Endocrine Reviews, 2002, 23(4), 443 63. 

Hartmann. G.. Cheung, A.K., and Piquette-Miller. M. (2002) Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia. 

As described in the previous section, bile acids have evolved over the last years from regulators of bile acid homeostasis to general metabolic integrators. It is therefore not too surprizing that a number of bile acid-activated signaling pathways have become attractive targets for the treatment of gallstones and other metabolic diseases, such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. 

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. 

Cholestyramine, colestipol, and colesevelam are the bile acidbinding resins or sequestrants (BAS) currently available in the United States. Resins are highly charged molecules that bind to bile adds (which are produced from cholesterol) in the gut. The resin-bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol resulting in an up-regulation of LDL receptors to replenish hepatocellular stores which then result in a decrease in serum cholesterol. Resins have been shown to reduce CHD events in patients without CHD.26... 

Chignard N, Mergey M, Veissiere D, Parc R, Capeau J, Poupon R et al. Bile acid transport and regulating functions in the human biliary epithelium. Hepatology 2001 33(3)496-503. 

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

Farnesoid X receptor (FXR) and liver X receptors (LXRs) belong to the same NR family as PXR and CAR. Their primary role lies in cholesterol and bile acid metabolism regulation. Like many NRs of this family, FXR heterodimerizes with RXR in vivo [46]. 

Its target genes regulate the secretion of bile acids and phospholipids into bile (bile salt efflux pump, MDR2 and 3), the intestinal reabsorption of bile add (ileal bile... 

In addition to the common pathways, glycolysis and the TCA cycle, the liver is involved with the pentose phosphate pathway regulation of blood glucose concentration via glycogen turnover and gluconeogenesis interconversion of monosaccharides lipid syntheses lipoprotein formation ketogenesis bile acid and bile salt formation phase I and phase II reactions for detoxification of waste compounds haem synthesis and degradation synthesis of non-essential amino acids and urea synthesis. 

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases... 

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