Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α
Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α
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DOI：
10.1074/jbc.m302287200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
Nebb, HI
中科院分区：
文献类型：
--
作者：
Dalen, KT;Ulven, SM;Nebb, HI
胰岛素响应性葡萄糖转运蛋白GLUT 4在胰岛素介导的促进葡萄糖摄取到脂肪组织和肌肉中起关键作用，并且GLUT 4的表达受损与肥胖和糖尿病有关。在这项研究中，我们表明，肝脏X受体（LXRs）调节GLUT 4的表达，通过直接与GLUT 4启动子中的保守LXR反应元件相互作用。在野生型、LXR α（-/-）和LXR β（-/-）小鼠中，WAT中GLUT 4的表达由强效LXR激动剂诱导，但在LXR α（-/-）β（-/-）小鼠中不诱导，表明两种LXR均能够介导GLUT 4基因的配体激活转录。然而，基础和胰岛素刺激的GLUT 4在附睾WAT中的表达仅在携带LXR α同种型消融的小鼠中减少。此外，GLUT 4的表达与小鼠和人脂肪细胞分化期间LXR α的诱导相关。因此，LXR β显然不能在LXR α不存在的情况下挽救GLUT 4的基础表达。我们先前已经证明LXR α在肥胖和糖尿病动物模型中下调，从而揭示了胰岛素抵抗条件下GLUT 4和LXR α表达之间的显著相关性。这表明LXR α亚型在GLUT 4的脂肪表达中具有独特的作用，并表明LXR α脂肪组织表达的改变可能是使糖尿病和胰岛素抵抗条件下失调的基因表达正常化的新工具。
The insulin-responsive glucose transporter GLUT4 plays a crucial role in insulin-mediated facilitated glucose uptake into adipose tissue and muscle, and impaired expression of GLUT4 has been linked to obesity and diabetes. In this study, we demonstrate that liver X receptors (LXRs) regulate the expression of GLUT4 through direct interaction with a conserved LXR response element in the GLUT4 promoter. The expression of GLUT4 in WAT is induced by a potent LXR agonist in wild type, LXRalpha(-/-), and LXRbeta(-/-) mice but not in LXRalpha(-/-) beta(-/-) mice, demonstrating that both LXRs are able to mediate ligand activated transcription of the GLUT4 gene. However, basal and insulin stimulated expression of GLUT4 in epididymal WAT is reduced only in mice carrying ablation of the LXRalpha isoform. The expression of GLUT4 is furthermore correlated to the induction of LXRalpha during mouse and human adipocyte differentiation. LXRbeta is thus apparently not able to rescue basal expression of GLUT4 in the absence of LXRalpha. We have previously demonstrated that LXRalpha is downregulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXRalpha expression in insulin-resistant conditions. This suggests that the LXRalpha isoform has a unique role in adipose expression of GLUT4 and suggests that alteration of adipose tissue expression of LXRalpha might be a novel tool to normalize the expression of a gene that is dysregulated in diabetic and insulin-resistant conditions.