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Text
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URL Address
<a href="http://doi.org/10.1002/hep.22627" target="_blank" rel="noreferrer noopener">http://doi.org/10.1002/hep.22627</a>
Pages
297–305
Issue
1
Volume
49
Dublin Core
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Title
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Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
Publisher
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Hepatology (Baltimore, Md.)
Date
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2009
2009-01
Subject
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Butadienes/pharmacology; Carcinoma; Cell Line; Chenodeoxycholic Acid/*pharmacology; Cholesterol 7-alpha-Hydroxylase/*biosynthesis; Cytoplasmic and Nuclear/metabolism/physiology; DNA-Binding Proteins/metabolism; Fibroblast Growth Factor; Fibroblast Growth Factors/drug effects/*physiology; Gene Expression/drug effects; Hepatocellular/metabolism; Hepatocytes/metabolism; Humans; Isoxazoles/pharmacology; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Nitriles/pharmacology; Receptor; Receptors; Signal Transduction/drug effects; Transcription Factors/metabolism; Tumor; Type 4/antagonists & inhibitors
Creator
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Song Kwang-Hoon; Li Tiangang; Owsley Erika; Strom Stephen; Chiang John Y L
Description
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UNLABELLED: Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism. CONCLUSION: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers.
Identifier
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<a href="http://doi.org/10.1002/hep.22627" target="_blank" rel="noreferrer noopener">10.1002/hep.22627</a>
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2009
Butadienes/pharmacology
Carcinoma
Cell Line
Chenodeoxycholic Acid/*pharmacology
Chiang John Y L
Cholesterol 7-alpha-Hydroxylase/*biosynthesis
Cytoplasmic and Nuclear/metabolism/physiology
Department of Integrative Medical Sciences
DNA-Binding Proteins/metabolism
Fibroblast Growth Factor
Fibroblast Growth Factors/drug effects/*physiology
Gene Expression/drug effects
Hepatocellular/metabolism
Hepatocytes/metabolism
Hepatology (Baltimore, Md.)
Humans
Isoxazoles/pharmacology
Li Tiangang
Mitogen-Activated Protein Kinase 1/metabolism
Mitogen-Activated Protein Kinase 3/metabolism
NEOMED College of Medicine
Nitriles/pharmacology
Owsley Erika
Receptor
Receptors
Signal Transduction/drug effects
Song Kwang-Hoon
Strom Stephen
Transcription Factors/metabolism
Tumor
Type 4/antagonists & inhibitors