The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166560. doi: 10.1016/j.bbadis.2022.166560. Epub 2022 Sep 24.
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.
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 (rFGF4, 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. 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 significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4 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-induced hepatoprotection in primary hepatocytes and in mice with NASH.
rFGF4 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.
非酒精性脂肪性肝病（NAFLD）已成为一种与非酒精性脂肪性肝炎（NASH）、肝硬化和肝细胞癌（HCC）越来越相关的主要肝脏疾病。然而，目前尚无治疗 NAFLD 和 NASH 的批准疗法。成纤维细胞生长因子 4（FGF4）最近被证明是几种代谢疾病有前途的药物候选物。
用高脂肪饮食加高果糖/葡萄糖饮用水（HF/HFG，西式饮食）喂养 21 周的小鼠，每隔一天腹膜内注射非有丝分裂重组 FGF4（rFGF4，1.0mg/kg 体重）8 周。在含有高葡萄糖/棕榈酸（HG/PA）或 TNFα/环己烷（TNFα/CHX）的培养基中培养的原代小鼠肝细胞用 1.0μg/ml rFGF4 处理。测定组织病理学、脂质代谢、炎症、肝细胞凋亡和纤维化的参数变化。评估 Caspase6 活性和 AMPK 途径。
rFGF4 给药显著减轻了 Western 样饮食诱导的小鼠肝脂肪变性、炎症、肝损伤和纤维化。rFGF4 治疗减少了脂肪酸诱导的脂质堆积和脂毒性诱导的肝细胞凋亡，这与 Caspase6 切割和激活的抑制有关。用 Compound C 抑制 AMP 激活的蛋白激酶（AMPK）或缺乏 Ampk 可消除 rFGF4 对原代肝细胞和 NASH 小鼠的肝保护作用。
rFGF4 通过 AMPK 依赖性信号通路对 NASH 发挥显著的保护作用。我们的研究表明，FGF4 类似物可能对西式饮食诱导的 NASH 具有治疗潜力。
