Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.
Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.
复制标题
DOI：
10.1038/s41598-018-31560-w
复制
发表时间：
2018-08-30
影响因子：
4.6
通讯作者：
Xue B
中科院分区：
文献类型：
--
作者：
Rajan A;Shi H;Xue B
I类组蛋白脱乙酰酶抑制剂(HDACis)可增加全身能量消耗，减轻高脂饮食诱导的胰岛素抵抗。然而，目前还不清楚这是否直接通过激活棕色脂肪的产热作用来发挥作用。在这里，我们发现PAN-HDACi TSA对棕色脂肪基因的表达产生了矛盾的影响，因为它抑制了棕色脂肪细胞中UCP1、PPARγ和Prdm16的表达，而促进了其他棕色脂肪特异基因的表达，如Pgc1α、Pgc1β、Acox1和CeiA。进一步的研究表明，在处理的棕色脂肪细胞中，I类HDACi MS-275显著增加；而II类HDACi MC-1568显著降低Ucp1和其他棕色脂肪特异性基因的表达。芯片分析显示，在MS-275处理的棕色脂肪细胞中，Pgc1α启动子上的H3乙酰化增强；而MC-1568的作用与上调视网膜母细胞瘤蛋白(Rb)和增强Rb启动子上H3K27的乙酰化有关。功能丧失研究表明，Pgc1α的上调在很大程度上介导了I类HDACis对生热程序的刺激作用，而Rb的上调可能是II类HDAC抑制作用的原因。因此，我们的数据表明，I类和II类HDACis对棕色脂肪致热基因的表达具有不同的影响。
Class I histone deacetylase inhibitors (HDACis) enhance whole body energy expenditure and attenuate high fat diet-induced insulin resistance. However, it is not clear whether this is exerted directly through activating brown fat thermogenesis. Here, we find that pan-HDACi TSA exerts paradoxical effects on brown fat gene expression, as it inhibits the expression of Ucp1, Pparγ and Prdm16 in brown adipocytes, while promoting the expression of other brown fat-specific genes such as Pgc1α, Pgc1β, Acox1 and Cidea. Further studies indicate that class I HDACi MS-275 significantly increases; whereas class II HDACi MC-1568 markedly reduces, the expression of Ucp1 and other brown fat-specific genes in treated brown adipocytes. ChIP assay reveals an enhanced H3 acetylation at the Pgc1α promoter in MS-275-treated brown adipocytes; whereas the effect of MC-1568 is associated with up-regulation of retinoblastoma protein (Rb) and an enhanced acetylation of H3K27 at the Rb promoter. Loss of function studies indicate that Pgc1α up-regulation largely mediates the stimulatory effect of class I HDACis on the thermogenic program, whereas up-regulation of Rb may be responsible for the inhibitory effect of class II HDACis. Thus, our data suggest that class I and II HDACis have differential effects on brown fat thermogenic gene expression.
登录
查看更多内容
影响因子：
2.5
作者：
Cui X;Nguyen NL;Zarebidaki E;Cao Q;Li F;Zha L;Bartness T;Shi H;Xue B
通讯作者：
Xue B
影响因子：
37.8
作者：
Hill JO;Wyatt HR;Peters JC
通讯作者：
Peters JC
影响因子：
4.6
作者：
Chen YS;Wu R;Yang X;Kou S;MacDougald OA;Yu L;Shi H;Xue B
通讯作者：
Xue B
影响因子：
64.5
作者：
Cohen P;Levy JD;Zhang Y;Frontini A;Kolodin DP;Svensson KJ;Lo JC;Zeng X;Ye L;Khandekar MJ;Wu J;Gunawardana SC;Banks AS;Camporez JP;Jurczak MJ;Kajimura S;Piston DW;Mathis D;Cinti S;Shulman GI;Seale P;Spiegelman BM
通讯作者：
Spiegelman BM
影响因子：
--
作者：
HIMMSHAGEN, J;CUI, JY;CLAUS, TH
通讯作者：
CLAUS, TH