SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional actvity and is down-regulated in hyperinsulinemic obese mice
SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional actvity and is down-regulated in hyperinsulinemic obese mice
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DOI：
10.1074/jbc.m505392200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Sakai, J
中科院分区：
文献类型：
--
作者：
Iguchi, H;Ikeda, Y;Sakai, J
在肥胖相关的胰岛素抵抗中，胰岛通过增加分泌能力来补偿胰岛素抵抗。在这里，我们报告的性别决定区Y盒6（SOX 6），转录因子的高迁移率族盒超家族的成员，作为胰腺十二指肠同源框因子-1（PDX 1）的共阻遏物的鉴定。正常小鼠和正常饮食的遗传性肥胖ob/ob小鼠的长期高脂肪喂养方案均大幅降低了SOX 6 mRNA水平。有趣的是，我们发现SOX 6在成人胰腺胰岛素分泌β细胞中表达，并且SOX 6的过表达降低了葡萄糖刺激的胰岛素分泌，这伴随着ATP/ADP比率降低，Ca 2+动员，胰岛素原含量和胰岛素基因表达。在一个互补的方式，小干扰RNA的SOX 6消耗增加葡萄糖刺激的胰岛素分泌在胰岛素瘤小鼠MIN 6和大鼠INS-1 E细胞。这些作用可以通过我们的机制研究来解释，该研究表明SOX 6通过直接的蛋白质/蛋白质相互作用来抑制胰岛素II启动子的PDX 1刺激。此外，SOX 6逆转录病毒表达降低了胰岛素II基因启动子染色质中组蛋白H3和H4的乙酰化，表明SOX 6可能通过改变特定启动子的染色质结构来降低PDX 1刺激。这些结果表明，在β细胞中通过SOX 6和PDX 1协调的转录调节的扰动可能有助于β细胞适应肥胖相关的胰岛素抵抗。
In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca2+ mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.