替米沙坦抑制SOCS-3/SREBP-1c通路改善非酒精性脂肪性肝炎模型大鼠的胰岛素抵抗

目的 探讨替米沙坦对高脂饮食诱导的非酒精性脂肪性肝炎大鼠肝组织SOCS-3通路的抑制作用及对胰岛素抵抗的干预作用。方法 70只雄性SD大鼠随机分为A （20只，正常对照）、B （30只，模型对照）和C组（20只，实验干预）。A组大鼠喂以普通饲料，B和C组喂以高脂饲料；12周末随机处理B组10只，行正葡萄糖高胰岛素钳夹试验，证实IR-NASH造模成功（100%）后，B、C两组继续高脂喂养，并予C组大鼠替米沙坦每日5 mg/kg灌胃，16周末全部大鼠测血清IL-6、TG、TC、ALT、AST、空腹血糖（FBG）和血清胰岛素（FBI），并计算胰岛素抵抗指数；行正葡萄糖高胰岛素钳夹试验，肝组织HE肝脏病理学检查，半定量RT-PCR法检测肝组织SOCS-3和SREBP-1c mRNA表达水平。结果 高脂饮食12周大鼠进展为NASH。16周末，B组大鼠肝湿重显著高于A组，C则明显低于B组；B组出现血脂异常和IR，血清IL-6、肝脏SOCS-3 mRNA和SREBP-1c mRNA表达水平明显上调（与A组比较P<0.01），三者分别与稳态葡萄糖输注率（VGIR60-120）显著负相关（r=0.9248，P<0.0001；r=0.9011，P<0.0001；r=0.9739，P<0.0001）。替米沙坦干预后，肝功能和血脂异常明显改善，NASH病理明显好转，SOCS-3 mRNA和SREBP-1c mRNA较B组显著下调（P<0.01），同时VGIR60-120明显增高（r=0.9532，P<0.0001；r=0.9687，P<0.0001），表明IR明显改善；而此时IL-6仍高水平，与VGIR60-120、SOCS-3、SREBP-1c失去相关关系（r=0.0071，P=0.7238；r=0.0019，P=0.8560；r=0.0002，P=0.9586），而SOCS-3 mRNA和SREBP-1c mRNA仍显著相关（r=0.9439，P<0.0001）。结论 替米沙坦干预NASH大鼠可显著减改善肝功能和IR，其机制并非抑制炎症因子IL-6，而是下调肝脏SOCS-3、SREBP-1c的表达，从而改善糖脂代谢和NASH。

Telmisartan improves insulin resistance in the rats with nonalcoholic steatohepatitis by SOCS-3/SREBP-1c pathway

Objective To evaluate the effects of telmisartan by SOCS-3/SREBP-1c pathway and its efficacy of improving insulin resistance (IR) in rats with high-fat diet-induced nonalcoholic steatohepatitis (NASH). Methods A total of 70 SD male rats were assigned randomly into 3 groups:A (normal control, 20 rats, basic diet), B (model control, 30 rats, high-fat diet) and C (treatment with telmisartan, 20 rats, high-fat diet). After the IR-NASH model was made successfully, proved by 10 rats randomly from the group B with euglycemic hyperinsulinemic clamp technique (EHCT) and liver histology, the rats in the group C were intragastrically administrated telmisartan (5 mg/kg/d) for 4 weeks, and then all rats were tested with EHCT and sacrificed to test the blood chemistry, interleukin-6, homeostasis model assessment of insulin resistance, hepatic pathological analysis, and semiquantitative RT-PCR for determining SOCS-3 and SREBP-1c mRNA. Results Rats with high-fat diet developed steatohepatitis and insulin resistance at the 12th week and had more weight gain and higher liver index at the 16th week. IL-6, SOCS-3 and SREBP-1c mRNA expressions in the group B were up-regulated obviously, and each was positively correlated with the velocities of glucose infusion rates at 60~120 min. Blood chemistry and pathological observation in the group C were all improved; both SOCS-3 and SREBP-1c mRNA were down-regulated, and each negatively correlated with VGIR60-120, while serum IL-6 stayed at a high level. Conclusions Telmisartan can remarkably improve hepatic function and insulin resistance in rats with IR-NASH, the mechanisms of which would not be by path of reducing the secretion of IL-6, but by down-regulating the expressions of SOCS-3 and SREBP-1c mRNA.