Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.
Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.
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DOI：
10.1371/journal.pone.0104675
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wells JM
中科院分区：
文献类型：
--
作者：
Jonatan D;Spence JR;Method AM;Kofron M;Sinagoga K;Haataja L;Arvan P;Deutsch GH;Wells JM
SOX17是一个关键的转录调节因子，可以通过调节其他转录因子发挥作用，包括HNF1β和FOXA2，它们被认为是调节出生后β细胞功能的因子。有鉴于此，我们研究了SOX17在发育和出生后胰腺中的作用，并发现了SOX17在调节胰岛素分泌方面的新作用。胰腺中Sox17基因的缺失(Sox17-paLOF)对胰腺发育没有明显影响。然而，Sox17-paLOF小鼠的胰岛胰岛素原蛋白含量较高，胰岛素原转运异常，分泌细胞器扩张，表明Sox17-paLOF成年小鼠是糖尿病前期。与此一致的是，Sox17-paLOF小鼠更容易患上与年龄相关的高脂饮食诱导的高血糖和糖尿病。在使用Ins2-RTTA驱动的小鼠的成熟β细胞中过表达Sox17导致了胰岛素原的早熟分泌。在转录方面，SOX17似乎广泛地调节分泌网络，因为SOX17表达的24小时脉冲导致调节激素运输和分泌的因子的整体转录变化。最后，瞬时过表达SOX17能够逆转MODY4动物中观察到的胰岛素分泌缺陷，并恢复正常血糖。总之，这些数据表明，SOX17在调节胰岛素运输和分泌方面发挥了关键的新作用，而且SOX17调节的通路可能在治疗上用于改善糖尿病背景下的细胞功能。
SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.
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