Engineered FGF19[DELA]KLB protects against intrahepatic cholestatic liver injury in ANIT-induced and Mdr2-/- mice model

The major safety concern of the clinical application of wild type FGF19 (FGF19.sup.WT) emerges given that its extended treatment causes hepatocellular carcinoma. Therefore, we previously generated a safer FGF19 variant - FGF19.sup.[DELA]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.sup.[DELA]KLB ameliorates intrahepatic cholestasis. We found that, similar to that of FGF19.sup.WT, the chronic administration of FGF19.sup.[DELA]KLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19.sup.[DELA]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.sup.[DELA]KLB did not induce any tumorigenesis effects during its prolonged treatment. Together, our findings raise hope that FGF19.sup.[DELA]KLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis.