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Review
. 2009 Apr;50 Suppl(Suppl):S120-5.
doi: 10.1194/jlr.R800026-JLR200. Epub 2008 Sep 24.

Fifty years of advances in bile acid synthesis and metabolism

David W Russell  1
Affiliations
Review

Fifty years of advances in bile acid synthesis and metabolism

David W Russell. J Lipid Res. 2009 Apr.

Abstract

There are two major pathways that mammalian cells use to supply themselves with cholesterol, one involving the synthesis of sterols from acetyl-CoA and the other the metabolism of cholesterol-rich lipoprotein particles via receptor-mediated endocytosis. There also are several pathways that mammalian cells use to break down cholesterol, and these disposal pathways are equal in physiological importance to the supply pathways. A major catabolic route involves conversion of cholesterol into conjugated bile salts, a transformation mediated by 16 or more liver enzymes. This review highlights findings in cholesterol catabolism from the last five decades with special emphasis on advances in bile acid synthesis, transport, and regulation.

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Figures

Fig. 1.
Fig. 1.
Enzymes of bile acid synthesis. The 16 enzymes and the 17 reactions they catalyze in converting cholesterol into a conjugated bile salt are shown. Mutations causing human disease have been identified in the nine enzymes that are boxed in blue (adapted from Ref. 33). The structures of cholesterol and a generic conjugated bile salt are shown. R = OH or H; X = glycine or taurine.
Fig. 2.
Fig. 2.
The enterohepatic circulation and bile acid transporters. Conjugated bile salts are moved through the enterohepatic circulation by transporters located on the apical and basolateral surfaces of hepatocytes and enterocytes. Redrawn from Ref. .
Fig. 3.
Fig. 3.
Regulation of bile acid synthesis. Intermediates and endproducts of the bile acid pathway regulate the expression of two genes in the liver (cholesterol 7α-hydroxylase and sterol 12α-hydroxylase) that synthesize conjugated bile salts through intricate regulatory schemes involving nuclear receptors [farnesoid X receptor (FXR), short heterodimer partner (SHP), liver X receptor (LXR), liver receptor homolog (LRH), hepatocyte nuclear factor 4α (HNF4α)], polypeptide hormones (FGF15) produced in the gut, and hepatic cell surface receptors [fibroblast growth factor 4 receptor (FGFR4)/βKlotho]. See text for details.
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