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TNF-α诱导的胰岛素抵抗小鼠糖脂代谢变化的分子机制研究
Research of the Molecular Mechanism for the Glucose-Lipid Metabolism Change in TNF-Alpha Induced Insulin Resistant Mice
【作者】 石绍川；
【导师】 李伶；
【作者基本信息】 重庆医科大学 ， 临床检验诊断学， 2008， 硕士
【摘要】 目的:探讨TNF-α诱导的胰岛素抵抗(IR)小鼠糖脂代谢的变化及其分子机制。方法:将20只健康雄性C57BL/6J小鼠随机分为TNF-α干扰组(TNF组,n=10)和正常对照组(NC组, n=10),给予TNF组腹腔注射TNF-α(6μg/kg体重/天),NC组注射等体积生理盐水,共7天;取血浆及脂肪、肝脏组织样本。测定血浆Fins、FBG、TC、TG、FFAs等糖脂代谢一般指标;测定脂肪组织及肝脏组织中与葡萄糖、甘油三酯、胆固醇代谢相关的基因mRNA或(和)蛋白的表达变化以及核转录因子过氧化物酶体增殖物激活受体PPARs的表达变化并研究它们之间的相关性。结果: 1)血浆糖脂代谢一般指标测定结果:与NC组相比较,TNF组小鼠Fins、FBG明显升高(p<0.01),FFAs亦升高(p<0.05),TG、TC轻微升高,但无明显变化(p>0.05)。2)葡萄糖代谢相关基因的表达变化:TNF组脂肪组织脂联素mRNA和血浆脂联素蛋白表达下降(均p<0.01),脂肪组织visfatin mRNA和血浆visfatin蛋白表达降低(p<0.05和p<0.01),肝脏组织FGF-21 mRNA表达无明显变化(p>0.05)。3)甘油三酯代谢相关基因的表达变化:TNF组脂肪组织ATGL mRNA和蛋白表达均明显下降(p<0.01和p<0.05),而脂肪组织HSL mRNA、肝脏组织CPT-1 mRNA表达均无明显变化(均为p>0.05)。4)胆固醇代谢相关基因的表达变化:两组小鼠间肝脏组织SREBP-2、HMGCR、LDLR mRNA的表达无明显差异(均为p>0.05)。5)核转录因子过氧化物酶体增殖物激活受体PPARs的表达变化:TNF组脂肪组织PPARγmRNA表达明显减弱(p<0.05),与脂联素mRNA表达和ATGL mRNA表达显著正相关(p<0.01和p<0.05)。同时,肝脏组织PPARδmRNA表达明显减弱(p<0.05),肝脏组织PPARα、PPARγmRNA表达均无明显变化(均为p>0.05)。结论:TNF-α过表达下调脂肪组织脂联素、visfatin、ATGL等糖脂代谢相关基因以及脂肪组织中PPARγ、肝脏组织中PPARδ等PPARs家族基因的表达,其中对脂联素和ATGL转录的下调作用可能通过PPARγ途径。TNF-α对肝脏组织中HMGCR、SREBP-2、LDLR等胆固醇代谢相关基因表达的影响较小。
【Abstract】 Objective: To investigate the effects and the molecular mechanism of TNF-αinduced insulin resistance on the related genes of glucose-lipid metabolism in mice.Methods: Male C57BL/6J mice were randomly divided into 2 groups. The mice were given an intraperitoneal injection of TNF-α(TNF group , 6μg/kg/d ;n=10) and saline (NC group, n=10) for 7 days. After 7 days, we analyzed the in vivo role of TNF-αon some metabolism-related genes and adipocytokines in the development of insulin resistance.Results: 1) TNF-αtreament resulted in a marked increasing fasting blood glucose, insulin, free fatty acids (FFA) compared with NC group ( p< 0.01 and p < 0.05 seperately ), and a slightly increasing TG,TC compared with NC group (p >0 .05 ); 2) The adipocyte ADPN mRNA expression in adipose tissues and ADPN protein in plasma were decreased ( p< 0.01) ; visfatin mRNA expression in adipose tissues and visfatin protein in plasma were decreased ( p < 0.05 and p <0.01 seperately ) and FGF-21 mRNA expression in liver tissues was not significantly changed ( p> 0.05 ) ; 3) The ATGL mRNA expression and ATGL protein in adipose tissues were decreased (p<0.01 and p<0.05 seperately); HSL mRNA in adipose tissues and CPT-1 mRNA in liver tissues were not significantly changed(p>0.05). 4) The mRNA expression of SREBP-2 ,HMGCR,LDLR mRNA in liver tissues were not significantly changed(p>0.05). 5) The PPARγmRNA expression in adipose tissues were significantly decreased(P<0.05); the PPARδmRNA expression in liver tissues were significantly decreased(P<0.05); the PPARγand PPARαmRNA expression in liver tissues was not significantly changed(P>0.05). 6) In adipose tissues, PPARγand ADPN mRNA expression were significantly positively related(p<0.01), PPARγand ATGL mRNA expression were significantly positively related(p<0.05).Conclusion: TNFαdownregulates some glucose-lipid metabolism related genes such as ADPN,visfatin,ATGL in adipose and some PPARs family genes such as PPARγin adipose and PPARδin liver;the downregulation effects to ADPN and ATGL transcription might be through PPARγpathways. TNFαhad small influences to cholesterol metabolism related genes such as HMGCR,SREBP-2,LDLR in liver tissues.