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二甲双胍对非酒精性脂肪性肝炎大鼠肝损伤的改善作用
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| 篇名： | 二甲双胍对非酒精性脂肪性肝炎大鼠肝损伤的改善作用 |
| TITLE： | Improvement effect of metformin on liver injury in non-alcoholic steatohepatitis rats |
| 摘要： | 目的 探究二甲双胍（Met）调控磷脂酰肌醇3激酶/蛋白激酶B/血小板源性生长因子（PI3K/AKT/PDGF）信号通路对非酒精性脂肪性肝炎（NASH）大鼠肝损伤的影响。方法以高糖高脂饮食饲喂大鼠构建NASH模型，造模成功后随机分为模型组（Model组）、Met低剂量组（Met-L组，100mg/kg）、Met中剂量组（Met-M组，200mg/kg）、Met高剂量组（Met-H组，400mg/kg）、高剂量Met+PI3K激活剂组（Met-H+740Y-P组，400mg/kgMet+50mg/kg740Y-P），另设对照组（Control组），每组12只。各组大鼠每天灌胃/注射相应药物1次，连续6周。分析大鼠体重和肝指数变化；观察大鼠肝组织病理损伤[评估非酒精性脂肪性肝病活动度评分（NAS）]、脂质沉积（计算油红O阳性染色面积占比）和纤维化（计算胶原沉积分数）情况；检测大鼠血清和肝组织中炎症因子[白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）]水平以及血清中脂代谢[总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）]和肝功能[天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）]指标水平；检测大鼠肝组织中PI3K/AKT/PDGF信号通路相关蛋白和胱天蛋白酶3（Caspase-3）蛋白表达水平。结果与Control组比较，Model组大鼠体重和肝指数，血清中脂代谢和肝功能指标水平，血清和肝组织中IL-6、TNF-α水平，NAS，油红O阳性染色面积占比，胶原沉积分数，肝组织中PI3K、AKT蛋白磷酸化水平和PDGF、Caspase-3蛋白表达水平均显著升高（P＜0.05）；肝组织病理损伤严重，富含脂滴，胶原沉积明显。经Met干预后，大鼠上述定量指标和病理变化均显著改善（P＜0.05），且呈剂量依赖性（P＜0.05）。740Y-P可显著逆转高剂量Met对大鼠上述指标的改善作用（P＜0.05）。结论Met可改善NASH大鼠肝损伤，减轻炎症反应和肝纤维化，其作用机制可能与抑制PI3K/AKT/PDGF信号通路活性有关。 |
| ABSTRACT： | OBJECTIVE To investigate the effects of metformin （Met） on liver injury in non-alcoholic steatohepatitis （NASH） rats by regulating the PI3K/AKT/PDGF signaling pathway. METHODS NASH model was constructed by feeding rats with a high- glucose and high-fat diet， and assigned into Model group， Met low-dose group （Met-L group， 100 mg/kg）， Met medium-dose group （Met-M group， 200 mg/kg）， Met high-dose group （Met-H group， 400 mg/kg）， and high dose of Met+PI3K activator group （Met-H+740 Y-P group， 400 mg/kg Met+50 mg/kg 740 Y-P）， with 12 rats in each group. Another 12 rats were regarded as the Control group. Each group of rats was orally administered/injected with the corresponding medication once a day for 6 consecutive weeks. The changes in body weight and liver index of rats were recorded and analyzed. The pathological damage [evaluation of non-alcoholic fatty liver disease activity score （NAS）]， lipid deposition （calculation of the proportion of oil red O-positive staining area）， and fibrosis （calculation of collagen deposition score） were observed in liver tissue of rats. The levels of inflammatory factors [interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α）] in serum and liver tissue， the levels of serum lipid metabolism indicators [total cholesterol （TC）， triglyceride （TG）， and low-density lipoprotein cholesterol （LDL-C）] and liver function indicators [aspartate aminotransferase （AST） and alanine Δ 基金项目 武汉市知识创新专项项目（No.2022020801010588）； aminotransferase （ALT）] were measured. The expression levels of PI3K/AKT/PDGF signaling pathway-related proteins and Caspase-3 in liver tissue of rats were determined. RESULTS Compared with the Control group， body weight， liver index， the levels of serum lipid metabolism indicators and liver function indicators， the levels of IL-6 and TNF-α in serum and liver tissue， the NAS， the proportion of oil red O-positive staining area， the collagen deposition fraction， and the levels of phosphorylated PI3K and AKT proteins， as well as the expression levels of PDGF and Caspase-3 proteins in liver tissue， were all significantly increased （P＜0.05）. The liver tissue showed severe pathological damage， characterized by an abundance of lipid droplets and pronounced collagen deposition. After the intervention with Met， the aforementioned quantitative indicators and pathological changes in rats were significantly improved in a dose- dependent manner （P＜0.05）. 740 Y-P could reverse the improvement effects of high dose of Met on the above indexes of rats （P＜ 0.05）. CONCLUSIONS Met can improve liver damage， and alleviate inflammatory reactions and liver fibrosis of NASH rats， the mechanism of which may be associated with inhibiting PI3K/AKT/PDGF signaling pathway. |
| 期刊： | 2025年第36卷第07期 |
| 作者： | 吴霜；程海林；刘丹；肖婷；吴兴邦；李华东；胡旭东 |
| AUTHORS： | WU Shuang，CHENG Hailin，LIU Dan，XIAO Ting，WU Xingbang，LI Huadong，HU Xudong |
| 关键字： | 二甲双胍；非酒精性脂肪性肝炎；肝损伤；脂代谢；肝纤维化；PI3K/AKT/PDGF信号通路 |
| KEYWORDS： | metformin； non-alcoholic steatohepatitis； liver damage； lipid metabolism； liver fibrosis； PI3K/AKT/PDGF |
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