Engineered FGF19ΔKLB protects against intrahepatic cholestatic liver injury in ANIT-induced and Mdr2-/- mice model

Abstract

Abstract Background The major safety concern of the clinical application of wild type FGF19 (FGF19WT) emerges given that its extended treatment causes hepatocellular carcinoma. Therefore, we previously generated a safer FGF19 variant - FGF19ΔKLB, which have same effects on glycemic control and bile acid production but much less mitogenic activity. However, it remains unclear as to whether FGF19ΔKLB ameliorates intrahepatic cholestasis. Results We found that, similar to that of FGF19WT, the chronic administration of FGF19ΔKLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19ΔKLB on cholestatic liver damage are attributable, according to the following mechanistic investigation, to the reduction of BA production, liver inflammation, and fibrosis. More importantly, FGF19ΔKLB did not induce any tumorigenesis effects during its prolonged treatment. Conclusions Together, our findings raise hope that FGF19ΔKLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis.

Keywords

• FGF19
• Hepatocellular carcinoma
• Bile acids
• Intrahepatic cholestasis
• Inflammation