The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation.
The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation.
复制标题
DOI：
10.1002/hep.24471
复制
发表时间：
2011-09-02
期刊：
影响因子：
13.5
通讯作者：
Timchenko, Nikolai A.
中科院分区：
文献类型：
--
作者：
Jin, Jingling;Iakova, Polina;Jiang, Yanjun;Medrano, Estela E.;Timchenko, Nikolai A.
年龄使肝功能下降，导致与年龄有关的疾病的发展。SIRT1是sirtuins家族的一员，参与控制葡萄糖稳态和脂肪代谢。由于衰老的肝脏有葡萄糖和脂肪代谢的改变，我们研究了SIRT1在这些改变中的可能作用。我们发现，衰老的肝脏SIRT1表达降低，并且在部分肝切除术（PH）后失去了对SIRT1调节的适当控制。老年小鼠肝脏中SIRT1的下调是由CCAAT/增强子结合蛋白/组蛋白去乙酰化酶1 （C/EBPβ-HDAC1）复合物介导的，该复合物结合并抑制SIRT1启动子。在幼龄小鼠的肝脏中，SIRT1在PH后被激活，并在肝脏再生过程中支持高水平的葡萄糖和甘油三酯。然而，在老年小鼠中，C/ ebp β- hdac1介导的SIRT1启动子的抑制阻断了SIRT1的激活，导致肝脏再生过程中葡萄糖和甘油三酯水平降低。年轻小鼠肝脏中SIRT1的下调导致与老年小鼠肝脏中观察到的变化相似，而老年小鼠肝脏中SIRT1的正常化纠正了ph后葡萄糖和甘油三酯的水平。老年小鼠中SIRT1的正常化还通过消除C/EBPα-Brm复合物来改善肝脏再生。这些研究表明SIRT1的降低在年龄相关的肝功能障碍中起关键作用，并为手术切除后老年患者的肝功能纠正提供了潜在的工具。
Age declines liver functions, leading to the development of age-associated diseases. A member of the sirtuins family, SIRT1, is involved in the control of glucose homeostasis and fat metabolism. Because aging livers have alterations in glucose and fat metabolism, we examined a possible role of SIRT1 in these alterations. We found that aged livers have a reduced expression of SIRT1 and have lost proper control of the regulation of SIRT1 after partial hepatectomy (PH). Down-regulation of SIRT1 in the liver of old mice is mediated by CCAAT/Enhancer Binding Protein/histone deacetylase 1 (C/EBPβ-HDAC1) complexes, which bind to and repress the SIRT1 promoter. In the livers of young mice, SIRT1 is activated after PH and supports high levels of glucose and triglycerides during liver regeneration. In old mice, however, C/EBPβ-HDAC1–mediated repression of the SIRT1 promoter blocks activation of SIRT1, leading to low levels of glucose and triglycerides during liver regeneration. Down-regulation of SIRT1 in the livers of young mice resulted in alterations similar to those observed in the livers of old mice, whereas the normalization of SIRT1 in the livers of old mice corrects the levels of glucose and triglycerides after PH. The normalization of SIRT1 in old mice also improves liver regeneration via the elimination of the C/EBPα-Brm complex. These studies showed a critical role of the reduction of SIRT1 in age-associated liver dysfunctions and provide a potential tool for the correction of liver functions in old patients after surgical resections.
登录
查看更多内容
DOI：
10.18632/aging.100156
发表时间：
2010-06
期刊：
Aging
影响因子：
--
作者：
Herranz D;Serrano M
通讯作者：
Serrano M
影响因子：
16
作者：
Wang, HM;Iakova, P;Timchenko, NA
通讯作者：
Timchenko, NA
影响因子：
15.9
作者：
Wang, Guo-Li;Shi, Xiurong;Timchenko, Nikolai A.
通讯作者：
Timchenko, Nikolai A.
影响因子：
7.8
作者：
Jin J;Wang GL;Iakova P;Shi X;Haefliger S;Finegold M;Timchenko NA
通讯作者：
Timchenko NA
影响因子：
4
作者：
Johnson, PF
通讯作者：
Johnson, PF