Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):329-34. doi: 10.1016/j.bbrc.2010.11.028. Epub 2010 Nov 13.
During a state of fasting, the blood glucose level is maintained by hepatic gluconeogenesis. SIRT1 is an important metabolic regulator during nutrient deprivation and the liver-specific knockdown of SIRT1 resulted in decreased glucose production. We hypothesize that SIRT1 is responsible for the upregulation of insulin-suppressed gluconeogenic genes through the deacetylation of FOXO1. Treatment of primary cultured hepatocytes with resveratrol increased insulin-repressed PEPCK and G6Pase mRNA levels, which depend on SIRT1 activity. We found that the resveratrol treatment resulted in a decrease in the phosphorylation of Akt and FOXO1, which are independent of SIRT1 action. Fluorescence microscopy revealed that resveratrol caused the nuclear localization of FOXO1. In the nucleus, FOXO1 is deacetylated by SIRT1, which might make it more accessible to the IRE of the PEPCK and G6Pase promoter, causing an increase in their gene expression. Our results indicate that resveratrol upregulates the expression of gluconeogenic genes by attenuating insulin signaling and by deacetylating FOXO1, which are SIRT1-independent in the cytosol and SIRT1-dependent in the nucleus, respectively.
在禁食状态下，血糖水平通过肝糖异生来维持。SIRT1 是营养缺乏时重要的代谢调节因子，肝脏特异性敲低 SIRT1 导致葡萄糖生成减少。我们假设 SIRT1 通过去乙酰化 FOXO1 负责上调胰岛素抑制的糖异生基因。用白藜芦醇处理原代培养的肝细胞会增加胰岛素抑制的 PEPCK 和 G6Pase mRNA 水平，这依赖于 SIRT1 活性。我们发现白藜芦醇处理导致 Akt 和 FOXO1 的磷酸化减少，这独立于 SIRT1 作用。荧光显微镜显示白藜芦醇导致 FOXO1 的核定位。在核内，SIRT1 使 FOXO1 去乙酰化，这可能使其更容易接近 PEPCK 和 G6Pase 启动子的 IRE，从而增加它们的基因表达。我们的结果表明，白藜芦醇通过减弱胰岛素信号和去乙酰化 FOXO1 来上调糖异生基因的表达，这在细胞质中分别是 SIRT1 非依赖性和 SIRT1 依赖性的，而在核内则是 SIRT1 非依赖性的。
