Bile acids: regulation of synthesis
- Department of Integrative Medical Sciences, Northeastern Ohio University's Colleges of Medicine and Pharmacy, Rootstown, OH 44272
- 1To whom correspondence should be addressed. e-mail: jchiang{at}neoucom.edu
Abstract
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 4α and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7α-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.
- cholesterol 7α-hydroylase
- nuclear receptors
- farnesoid X receptor
- fibroblast growth factor 19
- cell signaling
- lipid metabolism
- cholesterol 7α-hydroxylase
- drug therapy
- cholestasis
- liver diseases
Footnotes
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- 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 7α-hydroylase
- CYP8B1
- sterol 12α-hydroxylase
- CYP27A1
- sterol 27 hydroxylase
- DCA
- deoxycholic acid
- FGF15
- fibroblast growth factor 15
- FGF19
- fibroblast growth factor 19
- FGFR4
- FGF receptor 4
- FTF
- α-fetoprotein transcription factor
- FXR
- farnesoid X receptor
- H3K9
- histone 3-Lys9
- HDAC
- histone deacetylase
- HGF
- hepatocyte growth factor
- HNF4α
- hepatocyte nuclear factor 4α
- 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
- PPARα
- peroxisome proliferator activated receptor α
- PGC-1α
- peroxisome proliferator-activated receptor γ coactivator 1α
- SHP
- small heterodimer partner
- TNFα
- tumor necrosis factor α
- VDR
- vitamin D receptor
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This work was supported by National Institutes of Health Grants DK-44442 and DK-58379. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
- Received March 27, 2009.
- Revision received April 2, 2009.
- Revision received April 3, 2009.
- Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.
