| First Author | Wang L | Year | 2022 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1868 |
| Issue | 12 | Pages | 166560 |
| PubMed ID | 36167161 | Mgi Jnum | J:329941 |
| Mgi Id | MGI:7355798 | Doi | 10.1016/j.bbadis.2022.166560 |
| Citation | Wang L, et al. (2022) A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway. Biochim Biophys Acta Mol Basis Dis 1868(12):166560 |
| abstractText | BACKGROUND & AIMS: 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. METHODS: 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( big up tri, openNT) (rFGF4( big up tri, openNT), 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 TNFalpha/cyclohexane (TNFalpha/CHX) were treated with 1.0 mug/ml rFGF4( big up tri, openNT). Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. RESULTS: Administration of rFGF4( big up tri, openNT) significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4( big up tri, openNT) 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( big up tri, openNT)-induced hepatoprotection in primary hepatocytes and in mice with NASH. CONCLUSION: rFGF4( big up tri, openNT) 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. |
