Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels
Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels
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DOI：
10.1074/jbc.272.48.30261
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发表时间：
1997-11-28
影响因子：
4.8
通讯作者：
Thorens, B
中科院分区：
文献类型：
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作者：
Gremlich, S;Bonny, C;Thorens, B
IDX-1（胰岛/十二指肠同源框-1）是在十二指肠和胰腺β和δ细胞中表达的转录因子，其是胰腺的胚胎发育所需的并且反式激活Glut 2、葡萄糖激酶、胰岛素和生长抑素基因，在这里，我们表明，暴露于棕榈酸的离体大鼠胰岛诱导IDX-1减少了70%。1 mRNA和蛋白质表达以及IDX-1对其Glut 2和胰岛素启动子的同源顺式调节元件的结合活性分别降低40%和65%。棕榈酸的抑制作用需要其线粒体氧化，因为它被肉毒碱棕榈酰转移酶I抑制剂溴棕榈酸阻止，棕榈酸对IDX-1的影响与GLUT 2和葡萄糖激酶表达在mRNA和蛋白水平上分别降低40%和25%相关，胰岛素和生长抑素mRNA表达也降低40%和60%，而胰高血糖素mRNA表达没有改变。胰高血糖素和胰高血糖素含量分别降低85%、55%和65%。同时，胰高血糖素强烈刺激总激素释放（13倍），而胰岛素和生长抑素仅略微增加这些结果表明，升高的脂肪酸水平1）负调节Idx-1表达; 2）降低由IDX-1反式激活的基因的表达，例如GLUT 2、葡萄糖激酶、胰岛素和生长抑素的表达;和3）导致胰高血糖素合成和分泌的重要增加。因此，脂肪酸对胰岛基因表达具有多效性作用，Idx-1表达的阴性对照可能是这些多重缺陷发展的初始事件。
IDX-1 (islet/duodenum homeobox-1) is a transcription factor expressed in the duodenum and pancreatic beta and delta cells, It is required for embryonic development of the pancreas and transactivates the Glut2, glucokinase, insulin, and somatostatin genes, Here we show that exposure of isolated rat pancreatic islets to palmitic acid induced a similar to 70% decrease in IDX-1 mRNA and protein expression as well as 40 and 65% decreases in the binding activity of IDX-1 for its cognate cis-regulatory elements of the Glut2 and insulin promoters, respectively, The inhibitory effect of palmitic acid required its mitochondrial oxidation since it was prevented by the carnitine palmitoyltransferase I inhibitor bromopalmitic acid, The palmitic acid effect on IDX-1 was correlated with decreases in GLUT2 and glucokinase expression of 40 and 25%, respectively, at both the mRNA and protein levels, Insulin and somatostatin mRNA expression was also decreased by 40 and 60%, whereas glucagon mRNA expression was not modified, After 48 h of exposure to fatty acids, total islet insulin, somatostatin, and glucagon contents were decreased by 85, 55, and 65%, respectively, At the same time, total hormone release was strongly stimulated (13-fold) for glucagon, whereas its was only marginally increased for insulin and somatostatin (1.5- and 1.7-fold, respectively), These results indicate that elevated fatty acid levels 1) negatively regulate Idx-1 expression; 2) decrease the expression of genes transactivated by IDX-1 such as those for GLUT2, glucokinase, insulin, and somatostatin; and 3) lead to an important increase in glucagon synthesis and secretion, Fatty acids thus have pleiotropic effects on pancreatic islet gene expression, and the negative control of Idx-1 expression may be an initial event in the development of these multiple defects.