厄贝沙坦对高血压合并糖尿病大鼠脂肪肝的治疗作用及机制探讨

The therapeutic effect and mechanism of irbesartan on fatty liver in diabetes-hypertension rats

目的探讨厄贝沙坦对高血压合并糖尿病(SHDM)大鼠脂肪肝的治疗作用及对过氧化物酶体增殖物激活受体γ(PPAR-γ)介导AMPK/mTOR信号通路的影响。方法原发性高血压模型大鼠通过链脲佐菌素联合高糖高脂饲料建立SHDM大鼠模型。将模型大鼠随机分为模型组、厄贝沙坦组和厄贝沙坦+PPAR-γ抑制剂组,另设正常对照组。分别干预8周后,观察血压、血糖、血脂、肝功能以及肝脏病理的变化,检测肝组织PPAR-γ、AMPK/mTOR信号通路及自噬标志蛋白LC3B的表达情况,并利用电镜观察肝脏自噬小体的变化。结果与模型组相比,经厄贝沙坦治疗后,SHDM大鼠收缩压、血糖、血脂、肝功能及肝脏病理脂肪变均明显改善(P<0.05);但厄贝沙坦联合PPAR-γ抑制剂干预后,以上指标除血糖外,均再次升高,并且厄贝沙坦增加SHDM大鼠肝组织PPAR-γ表达和AMPK磷酸化水平,降低mTOR磷酸化水平,升高LC3BⅡ/Ⅰ比值和肝细胞自噬小体数量,与模型组相比,其差异均有统计学意义(P<0.05)。但是,加用PPAR-γ抑制剂后,以上效应被逆转。结论厄贝沙坦对SHDM大鼠脂肪肝有治疗作用,其作用机制与激活PPAR-γ介导的AMPK/mTOR信号通路,从而促进肝细胞自噬有关。

Objective To investigate the therapeutic effect of irbesartan on fatty liver in diabetes-hypertension(SHDM)rats and its influence on the AMPK/mTOR signaling pathway mediated by peroxisome proliferator-activated receptorγ(PPAR-γ).Methods The rat model of SHDM was induced by intraperitoneal injection of streptozotocin with high fat high sugar diet in spontaneously hypertensive rats.SHDM model rats were randomly divided into model group,irbesartan group and irbesartan+PPAR-γantagonist group.In addition,the normal rats were used as the normal control group.After 8 weeks of intervention,the changes of blood pressure,blood glucose,blood lipid,liver function and liver pathology were observed.The expression levels of PPAR-γ,AMPK/mTOR pathway molecules and LC3B in liver tissues were detected by Western blot assay,and the autophagosomes in the liver were observed under electron microscope.Results Compared with the model group,the systolic blood pressure,blood glucose,blood lipid,liver function and liver pathology were significantly ameliorated in irbesartan group(P<0.05).However,the above indexes except for the blood glucose were all increased after treatment with irbesartan and PPAR-γinhibitor.Importantly,the protein levels of PPAR-γ,p-AMPK and the LC3BⅡ/Ⅰratio were increased with irbesartan administration,while the expression of p-mTOR was decreased(P<0.05),which resulted in a distinct increase in LC3BⅡ/Ⅰratio and autophagosomes.There were significant differences in these indicators between model group and irbesartan group(P<0.05).However,these effects were reversed after treatment with irbesartan and PPAR-γinhibitor treatment.Conclusion Irbesartan has a therapeutic effect on fatty liver in SHDM rats,and its mechanism is related to the activation of PPAR-mediated AMPK/mTOR pathway,thereby promoting hepatocyte autophagy.