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Journal of Lipid Research, Vol. 50, 1955-1966, October 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Bile Acids

Bile acids: regulation of synthesis

John Y. L. Chiang¹

Department of Integrative Medical Sciences, Northeastern Ohio University's Colleges of Medicine and Pharmacy, Rootstown, OH 44272

¹ To whom correspondence should be addressed. e-mail: jchiang{at}neoucom.edu

Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4 and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.

Supplementary key words cholesterol 7-hydroylase • nuclear receptors • farnesoid X receptor • fibroblast growth factor 19 • cell signaling • lipid metabolism • cholesterol 7-hydroxylase • drug therapy • cholestasis • liver diseases

Abbreviations: ASBT, apical sodium-dependent bile acid transporter; BACS, bile acid:CoA synthase; BARE, bile acid response element; BAT, bile acid:amino acid transferase; BSEP, bile salt export pump; CA, cholic acid; CAR, constitutive androstane receptor; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7-hydroylase; CYP8B1, sterol 12-hydroxylase; CYP27A1, sterol 27 hydroxylase; DCA, deoxycholic acid; FGF15, fibroblast growth factor 15; FGF19, fibroblast growth factor 19; FGFR4, FGF receptor 4; FTF, -fetoprotein transcription factor; FXR, farnesoid X receptor; H3K9, histone 3-Lys9; HDAC, histone deacetylase; HGF, hepatocyte growth factor; HNF4, hepatocyte nuclear factor 4; HSC, hepatic stellate cell; IBABP, ileal bile acid binding protein; IL-1β, interleuken-1β; LCA, lithocholic acid; LXR, liver orphan receptor; LRH-1, liver-related homolog-1; MAPK, mitogen-activated protein kinase; NTCP, Na⁺-dependent taurocholate cotransport peptide; OST, organic solute transporter; PXR, pregnane X receptor; PPAR, peroxisome proliferator activated receptor ; PGC-1, peroxisome proliferator-activated receptor coactivator 1; SHP, small heterodimer partner; TNF, tumor necrosis factor ; VDR, vitamin D receptor

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