Abstract
The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.
MeSH terms
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Animals
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Anthracenes / pharmacology
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Bile Acids and Salts / biosynthesis*
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Cell Line
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Cells, Cultured
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Chenodeoxycholic Acid / pharmacology
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Cholesterol 7-alpha-Hydroxylase / genetics*
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Cholesterol 7-alpha-Hydroxylase / metabolism
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Repression
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism*
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Fibroblast Growth Factors / pharmacology
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Gene Expression Regulation
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Hepatocytes / metabolism*
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Humans
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Isoxazoles / pharmacology
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JNK Mitogen-Activated Protein Kinases
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-jun / metabolism
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Receptors, Cytoplasmic and Nuclear
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Recombinant Proteins / pharmacology
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Response Elements
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Signal Transduction*
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Transcription Factors / agonists
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
Substances
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Anthracenes
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Bile Acids and Salts
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DNA-Binding Proteins
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FGF19 protein, human
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Isoxazoles
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Proto-Oncogene Proteins c-jun
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Receptors, Cytoplasmic and Nuclear
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Recombinant Proteins
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Transcription Factors
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farnesoid X-activated receptor
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Chenodeoxycholic Acid
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pyrazolanthrone
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Fibroblast Growth Factors
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Cholesterol 7-alpha-Hydroxylase
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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GW 4064