SREBP1 is required for the induction by glucose of pancreatic beta-cell genes involved in glucose sensing.
SREBP1 is required for the induction by glucose of pancreatic beta-cell genes involved in glucose sensing.
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DOI：
10.1194/jlr.m700533-jlr200
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发表时间：
2008-04
影响因子：
6.5
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Diraison F;Ravier MA;Richards SK;Smith RM;Shimano H;Rutter GA
先前的研究报道了高葡萄糖浓度下的胰岛培养对调节胰岛素分泌的积极和消极影响。在这里，我们在小鼠胰岛中重新研究了这个问题，并确定了脂质合成变化在葡萄糖影响中的作用。在升高的葡萄糖浓度下培养四天后，在删除甾醇调节元件结合蛋白-1 (SREBP1) 的 C57BL/6 小鼠或同窝小鼠的胰岛中检查葡萄糖刺激的胰岛素分泌 (GSIS) 和基因表达。对照胰岛在 30 mmol/l 和 8 mmol/l 葡萄糖浓度下的培养导致基础葡萄糖浓度 (3 mmol/l) 和刺激葡萄糖浓度 (17 mmol/l) 的分泌增强，并导致三酰甘油 (TG) 积累增强。这些变化与参与葡萄糖传感（Slc2a2、Gck、Abcc8、Kcnj11）、分化（Pdx1）和脂肪生成（Srebp1、Fas、Acc1、Scd1）的基因表达增加相关。当在 8 或 30 mmol/l 葡萄糖下培养时，与正常胰岛相比，SREBP1-/- 胰岛表现出 GSIS 和 TG 含量降低。相应地，在SREBP1-/-小鼠胰岛中不再观察到对照胰岛中上述基因的葡萄糖诱导。我们得出的结论是，在升高的葡萄糖浓度下，胰岛基因表达和胰岛素分泌的适应性变化需要SREBP1c依赖性基因介导的脂质合成的增强。
Previous studies have reported both positive and negative effects of culture of islets at high glucose concentrations on regulated insulin secretion. Here, we have reexamined this question in mouse islets and determined the role of changes in lipid synthesis in the effects of glucose. Glucose-stimulated insulin secretion (GSIS) and gene expression were examined in islets from C57BL/6 mice or littermates deleted for sterol regulatory element binding protein-1 (SREBP1) following four days culture at elevated glucose concentrations. Culture of control islets at 30 vs. 8 mmol/l glucose led to enhanced secretion at both basal (3 mmol/l) and stimulatory (17 mmol/l) glucose concentrations, and to enhanced triacylglycerol (TG) accumulation. These changes were associated with increases in the expression of genes involved in glucose sensing (Slc2a2, Gck, Abcc8, Kcnj11), differentiation (Pdx1), and lipogenesis (Srebp1, Fas, Acc1, Scd1). When cultured at either 8 or 30 mmol/l glucose, SREBP1-/- islets displayed reduced GSIS and TG content compared to normal islets. Correspondingly, glucose induction of the above genes in control islets was no longer observed in SREBP1-/- mouse islets. We conclude that enhanced lipid synthesis mediated by SREBP1c-dependent genes is required for the adaptive changes in islet gene expression and insulin secretion at elevated glucose concentrations.