Class II histone deacetylases downregulate GLUT4 transcription in response to increased cAMP signaling in cultured adipocytes and fasting mice.
Class II histone deacetylases downregulate GLUT4 transcription in response to increased cAMP signaling in cultured adipocytes and fasting mice.
复制标题
作者：
Weems JC;Griesel BA;Olson AL
胰岛素介导的葡萄糖摄入对促进性葡萄糖转运蛋白GLUT 4的水平高度敏感。GLUT 4表达的抑制与脂肪组织中的胰岛素抵抗相关。我们已经表明，分化依赖性GLUT 4转录的II类组蛋白脱乙酰酶（HDAC）的控制下。我们假设HDACs可能通过肾上腺素能激活调节脂肪细胞中的基因表达。为了验证这一假设，我们激活了3 T3-L1脂肪细胞和小鼠过夜禁食后的cAMP信号。染色质免疫沉淀实验显示HDAC 4/5与GLUT 4启动子在体内和体外响应于升高的cAMP的关联。在培养的脂肪细胞中通过小干扰RNA敲低HDAC阻止了cAMP依赖性的GLUT 4转录降低。HDAC 4/5向GLUT 4启动子的募集依赖于GLUT 4肝脏X受体（LXR）结合位点。用LXR激动剂处理细胞防止了GLUT 4转录的cAMP依赖性降低。LXR反应元件中的功能缺失突变是体外、禁食小鼠和饮食诱导肥胖小鼠中cAMP依赖性GLUT 4表达下调所必需的。这表明LXR信号传导的激活可以防止糖尿病和肥胖症中GLUT 4表达的丧失。
Insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative glucose transporter protein, GLUT4. Repression of GLUT4 expression is correlated with insulin resistance in adipose tissue. We have shown that differentiation-dependent GLUT4 transcription was under control of class II histone deacetylases (HDACs). We hypothesized that HDACs may regulate gene expression in adipocytes as a result of adrenergic activation. To test this hypothesis, we activated cAMP signaling in 3T3-L1 adipocytes and in mice after an overnight fast. Chromatin immunoprecipitation experiments showed the association of HDAC4/5 with the GLUT4 promoter in vivo and in vitro in response to elevated cAMP. Knockdown of HDACs by small interfering RNA in cultured adipocytes prevented the cAMP-dependent decrease in GLUT4 transcription. HDAC4/5 recruitment to the GLUT4 promoter was dependent on the GLUT4 liver X receptor (LXR) binding site. Treatment of cells with an LXR agonist prevented the cAMP-dependent decrease in GLUT4 transcription. A loss of function mutation in the LXR response element was required for cAMP-dependent downregulation of GLUT4 expression in vitro, in fasted mice, and in mice subjected to diet-induced obesity. This suggests that activation of LXR signaling can prevent loss of GLUT4 expression in diabetes and obesity.
登录
查看更多内容
影响因子：
4.1
作者：
CAMPS, M;CASTELLO, A;ZORZANO, A
通讯作者：
ZORZANO, A
影响因子：
16
作者：
Ghisletti, Serena;Huang, Wendy;Glass, Christopher K.
通讯作者：
Glass, Christopher K.
影响因子：
7.7
作者：
SINHA, MK;RAINERIMALDONADO, C;CARO, JF
通讯作者：
CARO, JF
影响因子：
4.8
作者：
Weems, Juston;Olson, Ann Louise
通讯作者：
Olson, Ann Louise
影响因子：
5.3
作者：
Chang, SR;McKinsey, TA;Olson, EN
通讯作者：
Olson, EN