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Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis
Open accessAbstract
The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7α-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.
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Metadata
- Authors
- Holt, J. A., Luo, G., Billin, A. N., Bisi, J., McNeill, Y. Y., Kozarsky, K. F., Donahee, M., Wang, D. Y., Mansfield, T. A., Kliewer, S. A., Goodwin, B., & Jones, S. A.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-06-18
- Volume
- 17
- Issue
- 13
- Pages
- 1581-1591
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2146012023
- Cited by
- 696
- References
- 5
- Type
- posted content
- Language
- en
- Open access
- diamond
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