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  

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

作　　者：刘复娜[1] 王素格[1] 沈毅慧[1] 蒋树林[1] 

机构地区：[1]河北医科大学附属第二医院河北省消化病研究所,石家庄050000

出　　处：《中国实验动物学报》2017年第3期281-288,共8页Acta Laboratorium Animalis Scientia Sinica

摘　　要：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。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.

关 键 词：非酒精性脂肪性肝炎 胰岛素抵抗 SOCS-3 SREBP-1C 替米沙坦 

分 类 号：Q95-33[生物学—动物学]