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Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Liver-specific activities of FGF19 require Klotho beta
Benjamin C Lin1, Manping Wang1, Craig Blackmore1
1Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080.
The Journal of Biological Chemistry
|July 14, 2007
Summary
Fibroblast growth factor 19 (FGF19) regulates liver functions. This study reveals that Klotho beta (KLB) is essential for FGF19 to bind FGFR4, enabling liver-specific signaling and gene regulation.
Area of Science:
- Endocrinology
- Molecular Biology
- Hepatology
Background:
- Hepatocyte function is regulated by fibroblast growth factors (FGFs).
- The specific molecular mechanisms of the FGF19 endocrine pathway, particularly its liver-specific activity, remain unclear.
- FGF19 binds to FGF receptor 4 (FGFR4), but receptor distribution alone does not explain FGF19's liver specificity.
Purpose of the Study:
- To elucidate the role of Klotho beta (KLB) in mediating FGF19 activity.
- To provide definitive evidence for KLB's requirement in FGF19 signaling and gene modulation.
- To understand the molecular basis of FGF19's liver-specific functions.
Main Methods:
- Investigated the expression patterns of FGFR4 and KLB in mouse organs.
- Administered FGF19 to mice to observe its effects on gene expression.
- Analyzed FGF19 binding to FGFR4, intracellular signaling, and downstream gene expression modulation in relation to KLB presence.
Main Results:
- FGFR4 is widely distributed in mice, while KLB expression is more restricted.
- Both FGFR4 and KLB are abundantly expressed in the liver.
- FGF19 injection in mice induced liver-specific c-Fos expression and repressed CYP7A1 expression.
Conclusions:
- Klotho beta (KLB) is definitively required for FGF19 binding to FGFR4, intracellular signaling, and gene expression modulation.
- The restricted expression of KLB, alongside FGFR4 in the liver, explains the tissue-specific activity of FGF19.
- KLB acts as a novel FGFR4 co-receptor essential for FGF19's liver-specific functions in regulating bile acid homeostasis and related pathways.
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