Journal
JOURNAL OF LIPID RESEARCH
Volume 50, Issue 10, Pages 1955-1966Publisher
ELSEVIER
DOI: 10.1194/jlr.R900010-JLR200
Keywords
cholesterol 7 alpha-hydroylase; nuclear receptors; farnesoid X receptor; fibroblast growth factor 19; cell signaling; lipid metabolism; cholesterol 7 alpha-hydroxylase; drug therapy; cholestasis; liver diseases
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Funding
- National Institutes of Health [DK-44442, DK-58379]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK058379, R56DK044442, R01DK044442, R37DK058379] Funding Source: NIH RePORTER
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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 alpha and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7 alpha-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.-Chiang, J. Y. L. Bile acids: regulation of synthesis. J. Lipid Res. 2009. 50: 1955-1966.
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