Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.
Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.
复制标题
DOI：
10.1126/science.1227166
复制
发表时间：
2013-01-11
期刊：
影响因子：
--
通讯作者：
Verdin E
中科院分区：
文献类型：
--
作者：
Shimazu T;Hirschey MD;Newman J;He W;Shirakawa K;Le Moan N;Grueter CA;Lim H;Saunders LR;Stevens RD;Newgard CB;Farese RV Jr;de Cabo R;Ulrich S;Akassoglou K;Verdin E
乙酰辅酶A和烟酰胺腺嘌呤二核苷酸（NAD+）的浓度影响组蛋白乙酰化，从而耦合细胞代谢状态和转录调控。我们报道了酮体d-β-羟基丁酸酯（βOHB）是一种内源性的、特异性的I类组蛋白去乙酰化酶（HDAC）抑制剂。给予外源性βOHB或禁食或热量限制，这两种与βOHB丰度增加相关的条件，都增加了小鼠组织中的整体组蛋白乙酰化。βOHB对HDAC的抑制与转录的整体变化相关，包括编码氧化应激抵抗因子FOXO 3A和MT 2的基因的变化。用βOHB处理细胞增加了Foxo 3a和Mt 2启动子处的组蛋白乙酰化，并且这两个基因都通过HDAC 1和HDAC 2的选择性消耗而被激活。与FOXO 3A和MT 2活性增加一致，用βOHB治疗小鼠可显著保护小鼠免受氧化应激。
Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.
登录
查看更多内容
影响因子：
15.9
作者：
OWEN, OE;REICHARD, GA;SHUMAN, CR
通讯作者：
SHUMAN, CR
影响因子：
56.9
作者：
Nemoto, S;Finkel, T
通讯作者：
Finkel, T
影响因子：
64.8
作者：
Kops, GJPL;Dansen, TB;Burgering, BMT
通讯作者：
Burgering, BMT
DOI：
10.1073/pnas.022631999
发表时间：
2002-01-22
影响因子：
11.1
作者：
Kang, HL;Benzer, S;Min, KT
通讯作者：
Min, KT
DOI：
10.1126/science.1164097
发表时间：
2009-05-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wellen KE;Hatzivassiliou G;Sachdeva UM;Bui TV;Cross JR;Thompson CB
通讯作者：
Thompson CB