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

By J. Holt, G. Luo, A. Billin, J. Bisi, Y. Y. McNeill, K. Kozarsky, M. Donahee, Da-Yuan Wang, T. Mansfield, S. Kliewer and 2 more. Genes & Development, 2003

718 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8dbc6a3d8efdfc56c0909a4d05356eeb7944e7c2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. J. Y. Chiang
2. A. Calkin
3. M. Mohammadi
4. Bart Staels
5. Johan Auwerx
6. P. Tontonoz

In Oncology

1. J. Y. Chiang
2. Johan Auwerx
3. P. Tontonoz
4. A. Calkin
5. David S. Wishart

Citations in the corpus

• Targeting bile-acid signalling for metabolic diseases (2008, background): “, and of the secreted growth factor, fibroblast growth factor 19 ( FGF19 ), which is known as Fgf15 in the mous”
• Bile acids: regulation of synthesis (2009, background): “They report that FGF19 activates receptor tyrosine kinase FGF receptor 4 (FGFR4) signaling to inhibit CYP7A1 mRNA expression levels in hepatocytes (126).”
• Structural basis for fibroblast growth factor receptor activation. (2005, background): “In the adult, FGFs continue to regulate tissue homeostasis but also play important roles in wound healing, tissue repair, cholesterol metabolism [47,48] and serum phosphate regulation [49–54].”
• Role of bile acids and bile acid receptors in metabolic regulation. (2009, background): “Further investigations pointed to the role of FXRmediated upregulation of FGF19 expression in human hepatocytes (114), and of FGF15 in murine intestine (129), initiating an autocrine/paracrine loop activating the FGF-receptor 4 (FGFR4).”