LRP16基因对3T3-L1脂肪细胞胰岛素抵抗的影响及分子机制
摘要
目的：研究人白血病相关蛋白16(Leukemia Related Protein16, LRP16)基因与核因子-κB (Nuclear Factor-κB,NF-κB)炎症通路的关系以及对3T3-L1脂肪细胞葡萄糖代谢和胰岛素信号转导通路的影响,探讨LRP16基因对3T3-L1脂肪细胞胰岛素敏感性的影响及其可能的分子机制。
方法：(1)利用脂质体转染技术构建过表达LRP16基因的3T3-L1前脂肪细胞系3T3-L1-LRP16及其对照细胞系3T3-L1-3.1,按常规方法培养并诱导分化成熟,干预组加100gM的NF-κB抑制剂吡咯烷二硫氨基甲酸(Pyrrolidine Dithiocarbamate, PDTC)孵育24小时(对照组加DMSO),用100nM胰岛素刺激30分钟。2-脱氧-[3H]-D-葡萄糖法检测过表达LRP16对3T3-L1脂肪细胞胰岛素刺激状态下葡萄糖摄取率的影响；Western Blot法检测上述细胞中过表达LRP16基因对胰岛素受体底物-1(Insulin Receptor Substrate, IRS-1)信号通路中的关键蛋白pIRS-1(Ser307)、pIRS-1(Tyr1179)、 PI3-K(p85)、pAkt(Ser473)、pAkt(Thr308)表达的影响。(2)分别提取成熟的3T3-L1-LRP16及3T3-L1-3.1脂肪细胞的总蛋白和核蛋白,应用Western Blot法检测NF-κB p65的表达,给予上述PDTC干预和胰岛素刺激,免疫荧光法检测其NF-κB p65蛋白的细胞内分布以了解核转位情况。凝胶电泳迁移率实验(Electrophoretic mobility shift assay,EMSA)结合Supershift实验检测3T3-L1-LRP16及3T3-L1-3.1脂肪细胞的NF-κB p65的DNA结合活性。将pNF-KB-Luc、pcDNA-3.1、pcDNA-3.1-LRP16、pRL-TK质粒共转染Hela细胞,双荧光素酶报告检测系统检测NF-κB-Luc相对荧光素酶活性以反映NF-κB的转录活性；用PDTC预孵育细胞24小时作为干预,重复共转染实验。(3)实时荧光定量PCR法检测成熟3T3-L1-LRP16及3T3-L1-3.1脂肪细胞炎症细胞因子肿瘤坏死因子α(Tumor Necrosis Factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)、白介素-1β(Interleukin-1β,IL-1β)的mRNA表达、ELISA法检测细胞培养上清中TNF-α、IL-6、IL-1β蛋白的水平。
结果：(1)过表达LRP16抑制3T3-L1脂肪细胞胰岛素刺激的葡萄糖摄取,上调pIRS-1(Ser307)蛋白的表达,下调pIRS-1(Tyr1179)、PI3-K(p85)、 pAkt(Ser473)、pAkt(Thr308)蛋白的表达,PDTC干预处理可改善上述LRP16对葡萄糖摄取及IRS-1信号通路的抑制性效应。(2)过表达LRP16增强3T3-L1脂肪细胞NF-κB p65核蛋白的DNA结合活性,促进NF-κB p65蛋白的核转位,增加NF-κB p65的核蛋白表达。LRP16剂量依赖性地增加Hela细胞NF-κB的转录活性,PDTC干预处理可以抑制LRP16对NF-κB p65的核蛋白水平、核转位、DNA结合活性和转录活性的增强效应。(3)过表达LRP16基因显著增加了脂肪细胞炎症因子的表达：3T3-L1-LRP16细胞中IL-6、IL-1p和TNF-αmRNA的表达水平分别是对照3T3-L1-3.1细胞的4.53、7.17、9.58倍(P<0.05),3T3-L1-LRP16细胞培养上清中的TNF-α、IL-6、IL-1β的蛋白浓度分别是对照3T3-L1-3.1细胞的1.54、1.78、2.13倍(P<0.05)。
结论：LRP16通过增强NF-κB转录、增加NF-κBp65的DNA结合活性、促进NF-κB核转位激活了NF-κB炎症通路,促进了脂肪细胞炎症因子的表达,干扰了IRS-1信号通路,导致3T3-L1脂肪细胞胰岛素抵抗。
Objective:To investigate the effects and possible molecular mechanisms of LRP16gene on insulin resistance in murine3T3-L1adipocytes.
Methods:(1) The LRP16gene over-expressing adipocyte cell line3T3-L1-LRP16and its control cell line3T3-L1-3.1were constructed using lipidosome transfection technology. They were cultured and induced for differentiating into adipocytes by regular method. Before the following experiments, the adipocytes were pretreated with or without100μM NF-κB inhibitor PDTC for24hours, then were incubated with100nM insulin for30minutes at37℃. The insulin-stimulated glucose uptake rates were determined by2-deoxy-[3H]-D-glucose assay. Expressions of key proteins in IRS-1signaling pathway such as pIRS-1Ser307), pIRS-1(Tyr1179), PI3-K(p85), pAkt(Ser473) and pAkt(Thr308), were detected by Western blot respectively.(2) Full-differentiated3T3-L1-LRP16and3T3-L1-3.1adipocytes, with or without pretreatment of100μM PDTC for24hours, were incubated with100nM insulin for30minutes. The protein contents of both nuclear NF-κB p65and total NF-κB p65were determined by Western blot assay. The intracellular distributions of NF-κB p65proteins in3T3-L1-3.1and3T3-L1-LRP16adipocytes were detected by immunofluorescence analysis. The contents of active NF-κB in the nuclear extracts prepared from3T3-L1-LRP16and3T3-L1-3.1adipocytes were determined by non-radioactive electrophoretic mobility shift assay (EMSA) and supershift assay to evaluate the DNA binding activity of NF-κB p65protein. Hela cells were transiently co-transfected with the structural expression vectors including pNF-icB-Luc, pcDNA-3.1-LRP16, pcDNA-3.1, and the internal control vector pRL-TK, followed by treatment of100μM PDTC. Then the NF-κB relative luciferase activity which reflected the transcriptional activity of NF-κB was detected using a Dual-luciferase Reporter Gene Assay system.(3) The mRNA expressions of inflammatory cytokines in3T3-L1-3.1and3T3-L1-LRP16adipocytes such as TNF-α, IL-6, IL-1β were measured by real-time quantitative PCR. The concentrations of TNF-α, IL-6, and IL-1β in the supernatants of cultured3T3-L1-3.1and3T3-L1-LRP16adipocytes were measured using ELISA kits.
Results:(1) Over-expression of LRP16gene significantly inhibited the insulin-stimulated glucose uptake in3T3-L1adipocytes:the levels of glucose uptake in3T3-L1-LRP16adipocytes were significantly reduced to45.7%of that in3T3-L1-3.1adipocytes (P<0.05). LRP16over-expression in3T3-L1adipocytes also increased the protein expression of pIRS-1(Ser307), but decreased the expressions of pIRS-1(Tyr1179), PI3-K(p85), pAkt(Ser473) and pAkt(Thr308). PDTC treatment abolished the above inhibitory effects of LRP16on insulin-stimulated glucose uptake and IRS-1signaling.(2) Over-expression of LRP16gene enhanced the DNA binding activity of NF-κB p65, EMS A showed the DNA binding activity of NF-κB p65in3T3-L1-LRP16adipocytes was2.6-fold of that in3T3-L1-3.1adipocytes. LRP16also promoted the nuclear translocation of NF-κB p65,and increased the expression of nuclear NF-κB p65protein in3T3-L1adipocytes. LRP16enhanced the transcriptional activity of NF-κB in a dose-dependent manner in Hela cells, which could be abolished by treatment with a NF-κB inhibitor of PDTC.(3) LRP16gene enhanced the expressions of inflammatory cytokines:the relative levels of IL-6, IL-1β and TNF-a mRNA transcripts in3T3-L1-LRP16adipocytes were4.53,7.17and9.58-fold of that in3T3-L1-3.1adipocytes, respectively (P<0.05). The concentrations of IL-6, IL-1β and TNF-α in the supernatants of cultured3T3-L1-LRP16adipocytes were1.54,1.78and2.13-fold of that in3T3-L1-3.1adipocytes, respectively (P<0.05).
Conclusions:LRP16gene enhanced the transcription of NF-κ, promoted the nuclear translocation and DNA binding of NF-κBp65, upregulated the expressions of inflammatory cytokines, subsequently impaired the IRS-1signaling pathway and induced insulin resistance in3T3-L1adipocytes.
方法：(1)利用脂质体转染技术构建过表达LRP16基因的3T3-L1前脂肪细胞系3T3-L1-LRP16及其对照细胞系3T3-L1-3.1,按常规方法培养并诱导分化成熟,干预组加100gM的NF-κB抑制剂吡咯烷二硫氨基甲酸(Pyrrolidine Dithiocarbamate, PDTC)孵育24小时(对照组加DMSO),用100nM胰岛素刺激30分钟。2-脱氧-[3H]-D-葡萄糖法检测过表达LRP16对3T3-L1脂肪细胞胰岛素刺激状态下葡萄糖摄取率的影响；Western Blot法检测上述细胞中过表达LRP16基因对胰岛素受体底物-1(Insulin Receptor Substrate, IRS-1)信号通路中的关键蛋白pIRS-1(Ser307)、pIRS-1(Tyr1179)、 PI3-K(p85)、pAkt(Ser473)、pAkt(Thr308)表达的影响。(2)分别提取成熟的3T3-L1-LRP16及3T3-L1-3.1脂肪细胞的总蛋白和核蛋白,应用Western Blot法检测NF-κB p65的表达,给予上述PDTC干预和胰岛素刺激,免疫荧光法检测其NF-κB p65蛋白的细胞内分布以了解核转位情况。凝胶电泳迁移率实验(Electrophoretic mobility shift assay,EMSA)结合Supershift实验检测3T3-L1-LRP16及3T3-L1-3.1脂肪细胞的NF-κB p65的DNA结合活性。将pNF-KB-Luc、pcDNA-3.1、pcDNA-3.1-LRP16、pRL-TK质粒共转染Hela细胞,双荧光素酶报告检测系统检测NF-κB-Luc相对荧光素酶活性以反映NF-κB的转录活性；用PDTC预孵育细胞24小时作为干预,重复共转染实验。(3)实时荧光定量PCR法检测成熟3T3-L1-LRP16及3T3-L1-3.1脂肪细胞炎症细胞因子肿瘤坏死因子α(Tumor Necrosis Factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)、白介素-1β(Interleukin-1β,IL-1β)的mRNA表达、ELISA法检测细胞培养上清中TNF-α、IL-6、IL-1β蛋白的水平。
结果：(1)过表达LRP16抑制3T3-L1脂肪细胞胰岛素刺激的葡萄糖摄取,上调pIRS-1(Ser307)蛋白的表达,下调pIRS-1(Tyr1179)、PI3-K(p85)、 pAkt(Ser473)、pAkt(Thr308)蛋白的表达,PDTC干预处理可改善上述LRP16对葡萄糖摄取及IRS-1信号通路的抑制性效应。(2)过表达LRP16增强3T3-L1脂肪细胞NF-κB p65核蛋白的DNA结合活性,促进NF-κB p65蛋白的核转位,增加NF-κB p65的核蛋白表达。LRP16剂量依赖性地增加Hela细胞NF-κB的转录活性,PDTC干预处理可以抑制LRP16对NF-κB p65的核蛋白水平、核转位、DNA结合活性和转录活性的增强效应。(3)过表达LRP16基因显著增加了脂肪细胞炎症因子的表达：3T3-L1-LRP16细胞中IL-6、IL-1p和TNF-αmRNA的表达水平分别是对照3T3-L1-3.1细胞的4.53、7.17、9.58倍(P<0.05),3T3-L1-LRP16细胞培养上清中的TNF-α、IL-6、IL-1β的蛋白浓度分别是对照3T3-L1-3.1细胞的1.54、1.78、2.13倍(P<0.05)。
结论：LRP16通过增强NF-κB转录、增加NF-κBp65的DNA结合活性、促进NF-κB核转位激活了NF-κB炎症通路,促进了脂肪细胞炎症因子的表达,干扰了IRS-1信号通路,导致3T3-L1脂肪细胞胰岛素抵抗。
Objective:To investigate the effects and possible molecular mechanisms of LRP16gene on insulin resistance in murine3T3-L1adipocytes.
Methods:(1) The LRP16gene over-expressing adipocyte cell line3T3-L1-LRP16and its control cell line3T3-L1-3.1were constructed using lipidosome transfection technology. They were cultured and induced for differentiating into adipocytes by regular method. Before the following experiments, the adipocytes were pretreated with or without100μM NF-κB inhibitor PDTC for24hours, then were incubated with100nM insulin for30minutes at37℃. The insulin-stimulated glucose uptake rates were determined by2-deoxy-[3H]-D-glucose assay. Expressions of key proteins in IRS-1signaling pathway such as pIRS-1Ser307), pIRS-1(Tyr1179), PI3-K(p85), pAkt(Ser473) and pAkt(Thr308), were detected by Western blot respectively.(2) Full-differentiated3T3-L1-LRP16and3T3-L1-3.1adipocytes, with or without pretreatment of100μM PDTC for24hours, were incubated with100nM insulin for30minutes. The protein contents of both nuclear NF-κB p65and total NF-κB p65were determined by Western blot assay. The intracellular distributions of NF-κB p65proteins in3T3-L1-3.1and3T3-L1-LRP16adipocytes were detected by immunofluorescence analysis. The contents of active NF-κB in the nuclear extracts prepared from3T3-L1-LRP16and3T3-L1-3.1adipocytes were determined by non-radioactive electrophoretic mobility shift assay (EMSA) and supershift assay to evaluate the DNA binding activity of NF-κB p65protein. Hela cells were transiently co-transfected with the structural expression vectors including pNF-icB-Luc, pcDNA-3.1-LRP16, pcDNA-3.1, and the internal control vector pRL-TK, followed by treatment of100μM PDTC. Then the NF-κB relative luciferase activity which reflected the transcriptional activity of NF-κB was detected using a Dual-luciferase Reporter Gene Assay system.(3) The mRNA expressions of inflammatory cytokines in3T3-L1-3.1and3T3-L1-LRP16adipocytes such as TNF-α, IL-6, IL-1β were measured by real-time quantitative PCR. The concentrations of TNF-α, IL-6, and IL-1β in the supernatants of cultured3T3-L1-3.1and3T3-L1-LRP16adipocytes were measured using ELISA kits.
Results:(1) Over-expression of LRP16gene significantly inhibited the insulin-stimulated glucose uptake in3T3-L1adipocytes:the levels of glucose uptake in3T3-L1-LRP16adipocytes were significantly reduced to45.7%of that in3T3-L1-3.1adipocytes (P<0.05). LRP16over-expression in3T3-L1adipocytes also increased the protein expression of pIRS-1(Ser307), but decreased the expressions of pIRS-1(Tyr1179), PI3-K(p85), pAkt(Ser473) and pAkt(Thr308). PDTC treatment abolished the above inhibitory effects of LRP16on insulin-stimulated glucose uptake and IRS-1signaling.(2) Over-expression of LRP16gene enhanced the DNA binding activity of NF-κB p65, EMS A showed the DNA binding activity of NF-κB p65in3T3-L1-LRP16adipocytes was2.6-fold of that in3T3-L1-3.1adipocytes. LRP16also promoted the nuclear translocation of NF-κB p65,and increased the expression of nuclear NF-κB p65protein in3T3-L1adipocytes. LRP16enhanced the transcriptional activity of NF-κB in a dose-dependent manner in Hela cells, which could be abolished by treatment with a NF-κB inhibitor of PDTC.(3) LRP16gene enhanced the expressions of inflammatory cytokines:the relative levels of IL-6, IL-1β and TNF-a mRNA transcripts in3T3-L1-LRP16adipocytes were4.53,7.17and9.58-fold of that in3T3-L1-3.1adipocytes, respectively (P<0.05). The concentrations of IL-6, IL-1β and TNF-α in the supernatants of cultured3T3-L1-LRP16adipocytes were1.54,1.78and2.13-fold of that in3T3-L1-3.1adipocytes, respectively (P<0.05).
Conclusions:LRP16gene enhanced the transcription of NF-κ, promoted the nuclear translocation and DNA binding of NF-κBp65, upregulated the expressions of inflammatory cytokines, subsequently impaired the IRS-1signaling pathway and induced insulin resistance in3T3-L1adipocytes.
引文
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1. Quinn L. Type 2 diabetes:epidemiology, pathophysiology, and diagnosis. Natrs Clin North Am.2001,36:175-192
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