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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability
Jianlou Niu1, Jing Zhao1,2, Jiamin Wu1
1School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China.
Abstract:
As a physiological regulator of bile acid homeostasis, FGF19 is also a potent insulin sensitizer capable of normalizing plasma glucose concentration, improving lipid profile, ameliorating fatty liver disease, and causing weight loss in both diabetic and diet-induced obesity mice. There is therefore a major interest in developing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease. However, the known tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its clinical potential. Here, we show that nonmitogenic FGF19 variants that retain the full beneficial glucose-lowering and bile acid regulatory activities of WT FGF19 (FGF19WT) can be engineered by diminishing FGF19's ability to induce dimerization of its cognate FGF receptors (FGFR). As proof of principle, we generated three such variants, each with a partial defect in binding affinity to FGFR (FGF19ΔFGFR) and its coreceptors, i.e., βklotho (FGF19ΔKLB) or heparan sulfate (FGF19ΔHBS). Pharmacological assays in WT and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control and regulating bile acid synthesis. This approach provides a robust framework for the development of safer and more efficacious FGF19 analogs.
Insights
Fibroblast Growth Factor 19 (FGF19) analogs were engineered to reduce tumor risk while maintaining therapeutic benefits for diabetes and liver disease. These nonmitogenic variants show promise for safer FGF19-based treatments.
Area of Science:
- Biochemistry
- Endocrinology
- Hepatology
Background:
- Fibroblast Growth Factor 19 (FGF19) regulates bile acid homeostasis and improves metabolic parameters.
- FGF19 shows therapeutic potential for type 2 diabetes and liver diseases but carries a tumorigenic risk.
- Mitogenic activity of FGF19 is linked to its receptor dimerization, a potential driver of adverse effects.
Purpose of the Study:
- To engineer nonmitogenic FGF19 variants with retained therapeutic activities.
- To reduce the tumorigenic potential of FGF19 for clinical applications.
- To develop safer and more effective FGF19 analogs for metabolic and liver diseases.
Main Methods:
- Engineered FGF19 variants with reduced binding affinity to FGFR and/or coreceptors (βklotho, heparan sulfate).
- Assessed mitogenic activity of FGF19 variants.
- Evaluated glycemic control and bile acid regulatory functions in WT and db/db mice.
Main Results:
- Generated FGF19 variants (FGF19ΔFGFR, FGF19ΔKLB, FGF19ΔHBS) with significantly reduced mitogenic potential.
- These variants maintained the glucose-lowering and bile acid-regulating efficacy of wild-type FGF19 (FGF19WT).
- Pharmacological assays confirmed comparable metabolic benefits without increased mitogenicity.
Conclusions:
- Nonmitogenic FGF19 variants can be developed by modulating FGFR dimerization.
- Engineered FGF19 analogs retain beneficial metabolic and bile acid effects while losing mitogenic activity.
- This strategy offers a pathway for developing safer FGF19-based therapeutics for diabetes and liver conditions.
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