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Genes Dev. 2003 Jul 1;17(13):1581-91. Epub 2003 Jun 18.

Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.

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  • 1Nuclear Receptor Discovery Research, High Throughput Biology, Gene Interference, Transgenics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA .


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.

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