Dalen Knut Tomas, Ulven Stine Marie, Bamberg Krister, Gustafsson Jan-Ake, Nebb Hilde I
Institute for Nutrition Research, University of Oslo, N-0316 Oslo, Norway.
J Biol Chem. 2003 Nov 28;278(48):48283-91. doi: 10.1074/jbc.M302287200. Epub 2003 Sep 11.
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, LXR alpha-/-, and LXR beta-/- mice but not in LXR alpha-/-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 LXR alpha isoform. The expression of GLUT4 is furthermore correlated to the induction of LXR alpha during mouse and human adipocyte differentiation. LXR beta is thus apparently not able to rescue basal expression of GLUT4 in the absence of LXR alpha. We have previously demonstrated that LXR alpha is down-regulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXR alpha expression in insulin-resistant conditions. This suggests that the LXR alpha isoform has a unique role in adipose expression of GLUT4 and suggests that alteration of adipose tissue expression of LXR alpha might be a novel tool to normalize the expression of a gene that is dysregulated in diabetic and insulin-resistant conditions.
胰岛素反应性葡萄糖转运体GLUT4在胰岛素介导的促进葡萄糖摄取进入脂肪组织和肌肉过程中发挥关键作用，而GLUT4表达受损与肥胖症和糖尿病相关。在本研究中，我们证明肝脏X受体（LXRs）通过与GLUT4启动子中保守的LXR反应元件直接相互作用来调节GLUT4的表达。在野生型、LXRα-/-和LXRβ-/-小鼠中，强效LXR激动剂可诱导白色脂肪组织（WAT）中GLUT4的表达，但在LXRα-/-β-/-小鼠中则不然，这表明两种LXR均能够介导配体激活的GLUT4基因转录。然而，仅在敲除LXRα亚型的小鼠中，附睾WAT中GLUT4的基础表达和胰岛素刺激表达降低。此外，在小鼠和人类脂肪细胞分化过程中，GLUT4的表达与LXRα的诱导相关。因此，在缺乏LXRα的情况下，LXRβ显然无法挽救GLUT4的基础表达。我们之前已证明，在肥胖症和糖尿病动物模型中LXRα表达下调，从而揭示了在胰岛素抵抗状态下GLUT4与LXRα表达之间存在显著相关性。这表明LXRα亚型在脂肪组织中GLUT4的表达中具有独特作用，并表明改变脂肪组织中LXRα的表达可能是使在糖尿病和胰岛素抵抗状态下表达失调的基因正常化的一种新工具。
