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
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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。
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.
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。
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.
引文
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[3] Deacon CF.Therapeutic strategies based on glucagon-like peptide 1[J].Diabetes. 2004, 53(9):2181-2189.
[4] Ahrén B, Landin-Olsson M,Jansson PA,et al.Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes[J] . J Clin Endocrinol Metab. 2004, 89(5): 2078-2084.
[5] Esposito Katherine,Nappo Francesco,Marfella Raffade,et al.Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans:Role of oxidative stress.American Heart Association,2002,106:2067-2072.
[6] 王功玲,文芳,曹仁贤.肿瘤坏死因子-α 影响胰岛素信号传导的机制. 南华大学学报.医学版,2006,34(2):289-290.
[7] 严卫丽,顾东风 .Adiponectin 研究进展 . 国外医学内科学分册 ,2004, 31(l0):430-433.
[8] Ouchi N,Kihara S,AfitaY,et a1.Adipocyte—derived plasma pm—rein,adiponectin suppresses lipid accumulation and class A scavenger receptor expression in human monoeyte—derived macrophag.Circulation,200l,lo3(8):1057—1063.
[9] Mjlan G.C,ranzotto M,Scarda A,el a1.Resistin and adiponectin expression in visceral fat of obese rats:effect of weight loss.Obes Res,2002,10(11):1095-1103。
[10] 杨媚,杨刚毅.Visfatin 研究进展 .国际内分泌代谢杂志,2006,26(1):15-17.
[11] 刘建雷,李伶,杨刚毅. 成纤维细胞生长因子-21 的研究进展.检验医学与临床,2007,4(7):642-643.
[12] Wente W, Efanov AM, Brenner M,et al. Fibroblast growth factor-21 improvespancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes,2006,55 (9): 2470-2478.
[13] Alexei Kharitonenkov, Tatiyana L. Shiyanova, et al. FGF-21 as a novel metabolic regulator. J. Clin Invest, 2005,115(6):1627-1635.
[14] Pravenec M,Kazdova L,Landa V,et a1.Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hyperaensive rat.J Biol CherrI.2003,278:45209-45215.
[15] Brtmetti L,Orlando G.Recinella L,et a1.Resistin,but not adiponectin inhibits dopamine and norepinephrine release in the hypothalamus.Eur J Pharmacol,2004,493:41-44.
[16] Zimmermann R, Strauss JG, Haemmerle G,et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science,2004,306:1383–1386.
[17] Fredrikson G, Tornqvist H, Belfrage P. Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochim Biophys Acta 1986; 876:288–293.
[18] Holmquist M. Alpha/Beta-hydrolase fold enzymes: structures, functions and mechanisms. Curr Protein Pept Sci. 2000;1:209–235.
[19] Georg Schneider,Georg Neuberger,Michael Wildpaner,Sun Tian, Igor Berezovsky, Frank Eisenhaber:Application of a sensitive collection heuristic for very large protein families: Evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases. BMC Bioinformatics. 2006; 7: 164.
[20] Jocken JW, Langin D, Smit E , et al.Adipose triglyceride lipase and hormone-sensitive lipase protein expression is decreased in the obese insulin-resistant state. J Clin Endocrinol Metab. 2007 Jun;92(6):2292-9.
[21] Susan Kralisch , Johannes Klein b, Ulrike Lossner , et al. Isoproterenol, TNFα, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. Molecular and Cellular Endocrinology 240 (2005) :43–49.
[22] Lutz W. Weber, Meinrad Boll, Andreas Stampfl.Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins. World Journal of Gastroenterology,2004, 10(21):3081-3087.
[23] Brown MS, Goldstein JL . A receptor-mediated pathway for cholesterolhomeostasis[J].Science,1986,232:34-47.
[24] Laurenced Duvillard,Emmanuel Florentin,Gerard Lizard,et al.Cell surface expression of LDL receptor is decreased in type 2 diabetic patients and is normalized by insulin therapy[J].Diabetes care,2003,26(5):1540-1544.
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