A long-acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-adiponectin-IL17A pathway

Br J Pharmacol. 2018 Aug;175(16):3379-3393. doi: 10.1111/bph.14383. Epub 2018 Jul 3.


Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood*
  • Animals
  • Anti-Inflammatory Agents* / pharmacology
  • Anti-Inflammatory Agents* / therapeutic use
  • Blood Glucose / analysis
  • Body Weight / drug effects
  • Delayed-Action Preparations / pharmacology
  • Delayed-Action Preparations / therapeutic use
  • Disease Models, Animal
  • Fibroblast Growth Factors* / pharmacology
  • Fibroblast Growth Factors* / therapeutic use
  • Glucagon / blood
  • Insulin / blood
  • Interleukin-17 / blood*
  • Lipids / blood
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Signal Transduction


  • Adiponectin
  • Adipoq protein, mouse
  • Anti-Inflammatory Agents
  • Blood Glucose
  • Delayed-Action Preparations
  • Il17a protein, mouse
  • Insulin
  • Interleukin-17
  • Lipids
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Glucagon