Metformin (MET) and genistein (GEN) have a beneficial role in alleviating non-alcoholic fatty liver disease (NAFLD), but their combined effect on this disease has not yet been studied. The present study aimed to investigate the potential protective effects of combined MET and GEN on NAFLD in high-fat diet (HFD) fed mice. C57BL/6 male mice were fed on an HFD for 10 weeks. Animals were then divided into different groups and treated with MET (0.23%), GEN (0.2%) and MET+GEN (0.23% + 0.2%) for 3 months. Treatment with MET and GEN, alone or in combination significantly lowered body and liver weights and fasting blood glucose (FBG) in HFD mice. Combination therapy reduced liver triglyceride (TG) level and this effect was correlated with increased expression of carnitine palmitoyl transferase 1 (CPT1) gene, and reduced expression of fatty-acid synthase (FAS)and sterol regulatory element-binding protein-1c (SREBP-1c) genes. Combination therapy also affects gluconeogenesis pathway through decreasing expression of Glucose 6-phosphatase (G6Pase) and increasing phosphorylation of Glycogen synthase kinase 3β (GSK-3β). Furthermore, combination of MET and GEN ameliorates liver inflammation by switching macrophage into M2 phenotype, decreasing macrophage infiltration, reducing expression of pro-inflammatory cytokines and decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. In addition, combination therapy enhances phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Taken together, these findings suggest that the combination of MET and GEN have beneficial effects against NAFLD in HFD-fed model.

二甲双胍 (MET) 和染料木素 (GEN) 在减轻非酒精性脂肪肝 (NAFLD) 方面具有有益作用，但尚未研究它们对这种疾病的联合作用。本研究旨在调查 MET 和 GEN 组合对高脂肪饮食 (HFD) 喂养小鼠 NAFLD 的潜在保护作用。C57BL/6 雄性小鼠喂食 HFD 10 周。然后将动物分成不同的组并用 MET (0.23%)、GEN (0.2%) 和 MET+GEN (0.23% + 0.2%) 治疗 3 个月。MET 和 GEN 单独或联合治疗可显着降低 HFD 小鼠的体重和肝脏重量以及空腹血糖 (FBG)。联合治疗降低了肝脏甘油三酯 (TG) 水平，这种效果与肉碱棕榈酰转移酶 1 (CPT1) 基因的表达增加有关，和降低脂肪酸合酶 (FAS) 和甾醇调节元件结合蛋白-1c (SREBP-1c) 基因的表达。联合治疗还通过降低葡萄糖 6-磷酸酶 (G6Pase) 的表达和增加糖原合酶激酶 3β (GSK-3β) 的磷酸化来影响糖异生途径。此外，MET 和 GEN 的组合通过将巨噬细胞转变为 M2 表型、减少巨噬细胞浸润、减少促炎细胞因子的表达和降低活化 B 细胞 (NF-κB) 活性的核因子 kappa-轻链增强子来改善肝脏炎症。此外，联合治疗可增强 5' 腺苷单磷酸活化蛋白激酶 (AMPK) 的磷酸化。总之，这些发现表明 MET 和 GEN 的组合对 HFD 喂养模型中的 NAFLD 具有有益作用。