Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Diabetes. 2012 Jun;61(6):1404-14. doi: 10.2337/db11-0737. Epub 2012 Mar 8.
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.
胰岛素介导的葡萄糖摄取对易化葡萄糖转运蛋白 GLUT4 的水平高度敏感。GLUT4 表达的抑制与脂肪组织中的胰岛素抵抗有关。我们已经表明，依赖分化的 GLUT4 转录受 II 类组蛋白去乙酰化酶 (HDACs) 的控制。我们假设 HDACs 可能会由于肾上腺素能激活而调节脂肪细胞中的基因表达。为了验证这一假设，我们在 3T3-L1 脂肪细胞和禁食一夜后的小鼠中激活了 cAMP 信号。染色质免疫沉淀实验表明，在体内和体外，升高的 cAMP 会导致 HDAC4/5 与 GLUT4 启动子结合。在培养的脂肪细胞中用小干扰 RNA 敲低 HDACs 可防止 cAMP 依赖性 GLUT4 转录减少。HDAC4/5 募集到 GLUT4 启动子依赖于 GLUT4 肝 X 受体 (LXR) 结合位点。用 LXR 激动剂处理细胞可防止 cAMP 依赖性 GLUT4 转录减少。体外、禁食小鼠和饮食诱导肥胖小鼠中，LXR 反应元件的功能丧失突变对于 cAMP 依赖性 GLUT4 表达下调是必需的。这表明激活 LXR 信号可以防止糖尿病和肥胖症中 GLUT4 表达的丧失。
