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

Abstract

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^ΔKLB, which have same effects on glycemic control and bile acid production but much less mitogenic activity. However, it remains unclear as to whether FGF19^ΔKLB ameliorates intrahepatic cholestasis.

Results: We found that, similar to that of FGF19^WT, the chronic administration of FGF19^ΔKLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19^ΔKLB 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^ΔKLB did not induce any tumorigenesis effects during its prolonged treatment.

Conclusions: Together, our findings raise hope that FGF19^ΔKLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis.

Keywords: Bile acids; FGF19; Hepatocellular carcinoma; Inflammation; Intrahepatic cholestasis.