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

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

Automated summary

Our study found that similar to FGF19(WT), chronic administration of FGF19(Delta KLB) protected mice from cholestatic liver injury in two models. The therapeutic benefits of FGF19(Delta KLB) on cholestatic liver damage are attributed to reduced bile acid production, liver inflammation, and fibrosis. Importantly, FGF19(Delta KLB) did not induce tumorigenesis effects during prolonged treatment.