Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia*
Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia*
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DOI：
10.1074/jbc.m111.239418
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发表时间：
2011-05
期刊：
影响因子：
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通讯作者：
Adam B. Francisco;Rajni Singh;Haibo Sha;Xi Yan;Ling Qi;Xingen Lei;Q. Long
中科院分区：
文献类型：
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作者：
Adam B. Francisco;Rajni Singh;Haibo Sha;Xi Yan;Ling Qi;Xingen Lei;Q. Long
越来越多的证据表明内质网应激在2型糖尿病的发病机制中起重要作用。SEL1L是一种ER膜蛋白，在胰岛和腺泡细胞中高表达。我们最近报道，SEL1L的缺陷会导致全身性内质网应激，并导致小鼠胚胎死亡。在这里，我们表明，具有一个功能等位基因Sel1(Sel1+/−)的小鼠更容易患高脂饮食诱导的高血糖。Sel1+/−小鼠由于β细胞增殖减少，β细胞质量明显减少。因此，Sel1+/−小鼠存在严重的糖耐量不耐受，表现出明显的葡萄糖刺激的胰岛素分泌迟缓。在体外高浓度葡萄糖刺激下，Sel11+/−小鼠的胰岛表达的未折叠蛋白反应基因水平显著高于野生型对照小鼠。此外，在胰岛素瘤细胞系中，SEL1L功能的显性-负性干扰严重损害，而SEL1L的过表达则有效地促进蛋白质的分泌。综上所述，我们的结果表明，SEL1L单倍体不足使小鼠易患高脂饮食诱导的高血糖。我们的发现强调了SEL1L在调节成人β细胞功能和生长方面的一个关键和以前未知的功能。
Increasing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of type 2 diabetes mellitus. SEL1L is an ER membrane protein that is highly expressed in the pancreatic islet and acinar cells. We have recently reported that a deficiency of SEL1L causes systemic ER stress and leads to embryonic lethality in mice. Here we show that mice with one functional allele of Sel1l (Sel1l+/−) are more susceptible to high fat diet (HFD)-induced hyperglycemia. Sel1l+/− mice have a markedly reduced β-cell mass as a result of decreased β-cell proliferation. Consequently, Sel1l+/− mice are severely glucose-intolerant and exhibit significantly retarded glucose-stimulated insulin secretion. Pancreatic islets from Sel1l+/− mice stimulated with a high concentration of glucose in vitro express significantly higher levels of unfolded protein response genes than those from wild-type control mice. Furthermore, dominant-negative interference of SEL1L function in insulinoma cell lines severely impairs, whereas overexpression of SEL1L efficiently improves protein secretion. Taken together, our results indicate that haploid insufficiency of SEL1L predispose mice to high fat diet-induced hyperglycemia. Our findings highlight a critical and previously unknown function for SEL1L in regulating adult β-cell function and growth.