A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2022-12, Vol.1868 (12), p.166560, Article 166560
• Main Authors: Wang, Luyao, Dong, Wenliya, Gao, Huan, Chen, Chuchu, Liang, Siyu, Ye, Xianxi, Liu, Yi, Hou, Yushu, Fan, Lei, Pan, Tongtong, Wang, Zengshou, Chen, Yongping, Luo, Yongde, Song, Lintao
• Format: Article
• Language: English
• Subjects: AMP-activated protein kinase; Apoptosis; Fibrosis; Inflammation; NASH; Non-mitogenic fibroblast growth factor 4
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2022.166560

Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases. Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 μg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT–induced hepatoprotection in primary hepatocytes and in mice with NASH. rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH. •Non-mitogenic rFGF4△NT alleviates the pathological characteristics of NASH in mice given a HF/HFG diet.•The activated AMPK pathway is required for enabling the protective effects of rFGF4△NT against NASH.•rFGF4△NT may provide a potential safe and effective medical treatment for NASH in humans.