Non‐alcoholic steatohepatitis (NASH) is the most severe form of non‐alcoholic fatty liver disease and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. However, the disadvantages of FGF21 as a clinically useful medicine include its short plasma half‐life and poor drug‐like properties. Here, we have explored the effects of PsTag600‐FGF21, an engineered long‐acting FGF21 fusion protein, in mice with NASH and describe some of the underlying mechanisms.

A long‐acting FGF21 was prepared by genetic fusion with a 600 residues polypeptide (PsTag600). We used a choline‐deficient high‐fat diet‐induced model of NASH in mice. The effects on body weight, insulin sensitivity, inflammation and levels of hormones and metabolites were studied first. We further investigated whether PsTag600‐FGF21 attenuated inflammation through the Th17‐IL17A axis and the associated mechanisms.

PsTag600‐FGF21 dose‐dependently reduced body weight, blood glucose, and insulin and lipid levels and reversed hepatic steatosis. PsTag600‐FGF21 enhanced fatty acid activation and mitochondrial β‐oxidation in the liver. The profound reduction in hepatic inflammation in NASH mice following PsTag600‐FGF21 was associated with inhibition of IL17A expression in Th17 cells. Furthermore, PsTag600‐FGF21 depended on adiponectin to exert its suppression of Th17 cell differentiation and IL17A expression.

Our data have uncovered some of the mechanisms by which PsTag600‐FGF21 suppresses hepatic inflammation and further suggest that PsTag600‐FGF21 could be an effective approach in NASH treatment.