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

JA Holt, G Luo, AN Billin, J Bisi, YY McNeill… - Genes & …, 2003 - genesdev.cshlp.org
JA Holt, G Luo, AN Billin, J Bisi, YY McNeill, KF Kozarsky, M Donahee, TA Mansfield…
Genes & development, 2003genesdev.cshlp.org
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 …
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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