Coordinate regulation of Wnt signaling and transcriptional factors in endocrine pancreatic islets in obese related insulin

Wnt共同受体低密度脂蛋白受体相关蛋白5在骨积累和眼睛发育中起着重要作用。在肥胖相关的胰岛素抵抗中，胰岛通过增加其分泌量或增加胰岛细胞质量来补偿胰岛素抵抗。我们研究了Wnt/β-catenin信号在胰岛的表达。在这里，我们报道了转录因子HMG盒超家族成员SOX6作为胰腺-十二指肠同源盒因子-1(PDX1)的辅助抑制因子。长期高脂喂养使正常小鼠和正常饮食的肥胖小鼠的SOX6基因表达水平显著降低。SOX6的过度表达降低了葡萄糖刺激的胰岛素分泌(GSIS)，同时伴随着ATP/ADP比值、钙动员、胰岛素原含量和胰岛素基因表达的降低。以互补的方式，通过小干扰RNA去除SOX6可以增强胰岛素瘤小鼠MIN6和大鼠INS-1E细胞中的GSIS。这些效应可以由我们的机制研究解释，这些研究表明SOX6通过直接的蛋白质相互作用抑制PDX1对胰岛素II启动子的刺激。此外，SOX6逆转录病毒表达减少了胰岛素II基因启动子染色质中组蛋白H3和H4的乙酰化，这表明SOX6可能通过改变特定启动子的染色质结构来减少对PDX1的刺激。我们还发现，SOX6的过度表达导致线粒体氧化磷酸化相关基因的表达显著减少，其中大部分基因的表达被PDX1的过度表达相互上调，这表明SOX6也可能是其他PDX1依赖基因的通用共抑制因子。此外，我们还证实了SOX6通过与β-连环蛋白物理相互作用，募集组蛋白脱乙酰基酶1，从而抑制WNT/β-连环蛋白信号通路，抑制INS-1和NIH3T3细胞的增殖。

A Wnt coreceptor low density lipoprotein receptor related protein 5 plays an essential role in bone accrual and eye development. In obesity-related insulin resistance, the pancreatic islets compensate for insulin resistance by increasing their secretory capacity or increasing islet cell mass. We investigated Wnt/β-catenin signal in pancreatic islet. Here, we report the identification of SOX6, a member of the HMG 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 the genetically obese ob/ob mice on a normal chow diet.Overexpression of SOX6 decreased glucose stimulated insulin secretion (GSIS) which was accompanied by decreased ATP/ADP ratio, Ca^<2+> mobilization, proinsulin content and insulin genes expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented GSIS 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 the 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. We also show that SOX6 overexpression results in a marked reduction in the expression of genes involved in mitochondrial oxidative phosphorylation, most of which were reciprocally up-regulated by PDX1 overexpression, suggesting that SOX6 may also act as a general co-repressor of other PDX1 dependent genes. Furthermore, we also demonstrated that SOX6 inhibits Wnt/β-catenin signaling pathway by physically interacting with β-catenin, recruiting histone deacetylase 1 and reduces INS-1 and NIH3T3 cell proliferation.