Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner
Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner
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DOI：
10.2337/db06-0753
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发表时间：
2007-02-01
期刊：
影响因子：
7.7
通讯作者：
Lee, In-Kyu
中科院分区：
文献类型：
--
作者：
Park, Keun-Gyu;Lee, Kyeong-Min;Lee, In-Kyu
长期的血糖浓度升高会对β细胞功能产生有害影响。这种糖毒性的特征之一是胰岛素基因表达减少，这是由于胰岛素启动子活性降低所致。小异二聚体伙伴(SHP；NR0B2)是一种非典型的孤儿核受体，在多种代谢途径中抑制核受体信号转导。在这项研究中，我们发现在高糖浓度下持续培养INS-1细胞会导致SHP基因表达增加，随后胰岛素基因表达减少。通过小干扰RNA抑制内源性SHP基因的表达，部分恢复了高糖诱导的胰岛素基因抑制。腺病毒介导的SHP在INS-1细胞中的过表达抑制了葡萄糖刺激的胰岛素分泌和胰岛素基因的表达。SHP通过两种机制下调胰岛素基因的表达：通过下调PDX-1和MafA基因的表达，以及通过抑制p300介导的胰腺十二指肠同源盒因子1和β2依赖的胰岛素启动子转录活性。糖尿病OLETF大鼠胰岛表达SHP mRNA的水平高于LETO大鼠。这些结果提示，SHP在糖毒性所致的胰岛β细胞功能障碍的发生发展中起重要作用。
Prolonged elevations of glucose concentration have deleterious effects on beta-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose-induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1- and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of beta-cell dysfunction induced by glucotoxicity.