Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.
Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.
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发表时间：
1994-11
影响因子：
6.5
通讯作者：
May M. Chen;J. Breslow;Weihua Li;T. Leff
中科院分区：
文献类型：
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作者：
May M. Chen;J. Breslow;Weihua Li;T. Leff
胰岛素依赖型糖尿病（IDDM）与血浆甘油三酯水平升高有关，在胰岛素给药后，甘油三酯水平恢复正常。在转基因小鼠中apoC-III基因过表达可引起高甘油三酯血症的观察结果和其他证据提示apoC-III参与甘油三酯水平的调节，这促使我们研究apoC-III是否可能参与与IDDM相关的高甘油三酯血症。为此，在链脲佐菌素处理的IDDM小鼠模型中研究了apoC-III基因表达的调节。在胰岛素缺乏的糖尿病状态下，通过北方分析以及定量溶液杂交RNA酶保护测定，这些小鼠具有升高的葡萄糖和甘油三酯水平以及肝脏apoC-III mRNA水平的1.4至1.5倍增加。胰岛素治疗使葡萄糖和甘油三酯水平正常化，并使肝脏apoC-III mRNA水平降低59%。使用核连续技术分析转录率表明，肝脏apoC-III mRNA水平的变化是该基因转录活性变化的结果。为了确定胰岛素在apoC-III转录调节中的作用，用apoC-III报告基因构建体转染HepG 2细胞，并用不同浓度的胰岛素处理。结果表明，胰岛素治疗诱导apoC-III转录活性的剂量依赖性下调。这些数据表明，在动物中观察到的apoC-III转录变化是由胰岛素浓度的差异引起的。假设apoC-III mRNA水平反映了蛋白质的合成和分泌，这些结果表明apoC-III基因的过度表达可能导致在IDDM中观察到的高脂血症。
Insulin-dependent diabetes mellitus (IDDM) is associated with elevated plasma triglyceride levels that normalize after insulin administration. The observation that overexpression of the apoC-III gene in transgenic mice can cause hypertriglyceridemia and other evidence implicating apoC-III in the regulation of triglyceride levels prompted us to examine whether apoC-III might be involved in the hypertriglyceridemia associated with IDDM. To this end, the regulation of apoC-III gene expression was studied in the streptozotocin-treated mouse model of IDDM. In the insulin-deficient diabetic state, these mice have elevated glucose and triglyceride levels and a 1.4- to 1.5-fold increase in hepatic apoC-III mRNA levels, by Northern analysis as well as quantitative solution hybridization RNase protection assay. Insulin treatment normalized the glucose and triglyceride levels and diminished hepatic apoC-III mRNA levels by 59%. Analysis of transcription rates using the nuclear run-on technique demonstrated that the changes in hepatic apoC-III mRNA levels were the results of changes in the transcriptional activity of the gene. To determine the role of insulin in the regulation of apoC-III transcription, HepG2 cells were transfected with an apoC-III reporter construct, and treated with different insulin concentrations. The results demonstrated that insulin treatment induced a dose-dependent down-regulation of apoC-III transcriptional activity. These data suggest that the apoC-III transcriptional changes seen in animals are caused by differences in insulin concentrations. Assuming that apoC-III mRNA levels reflect the synthesis and secretion of the protein, these results present the possibility that overexpression of the apoC-III gene could contribute to the hypertriglyceridemia observed in IDDM.