Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis
Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis
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DOI：
10.2337/db15-0249
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发表时间：
2016-01-01
期刊：
影响因子：
7.7
通讯作者：
Choi, Hueng-Sik
中科院分区：
文献类型：
--
作者：
Lee, Ji-Min;Seo, Woo-Young;Choi, Hueng-Sik
胰高血糖素/cAMP依赖性蛋白激酶诱导型辅激活因子PGC-1信号通路在肝纤维化发生中的作用已得到充分表征。然而，相反的蛋白激酶B（PKB）/Akt诱导的辅抑制子信号通路尚不清楚。以前的报告已经证明，小异源二聚体伴侣相互作用亮氨酸拉链蛋白（SMILE）调节核受体和转录因子，控制肝细胞新生。在这里，我们表明，肝脏SMILE表达诱导喂养正常小鼠，但不是在db/db和高脂饮食（HFD）喂养的小鼠。有趣的是，SMILE表达诱导胰岛素在小鼠原代肝细胞和肝脏。在肝脏特异性胰岛素受体敲除（LIRKO）或PKB β缺陷（PKB β（-/-））小鼠中，肝脏SMILE表达未因再喂养而改变。在分子水平上，SMILE通过与PGC-1 α直接竞争抑制肝细胞核因子4介导的转录活性。此外，SMILE的消融增强了小鼠的血管生成并增加了血糖水平。相反，SMILE的过度表达降低了db/db和HFD喂养小鼠的肝脏致炎基因表达，并改善了高血糖和葡萄糖耐受不良。因此，SMILE是一种胰岛素诱导的辅阻遏物，可抑制肝细胞生成。增强SMILE表达的小分子具有治疗糖尿病高血糖症的潜力。
The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1 signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB beta-deficient (PKB beta(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1 alpha. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes.