Regulation of glucose transporter expression by PPARa

描述(由申请人提供)： 越来越多的证据表明，脂代谢紊乱在胰岛素抵抗和糖尿病的发生发展中起着重要作用。具体地说，高水平的循环脂肪酸会影响骨骼肌输入和利用葡萄糖的能力。最近的工作表明，核受体转录因子，过氧化物酶体增殖物激活受体a(PPARa)在糖尿病心脏中被激活，导致对葡萄糖运输和利用的反向调节，包括编码胰岛素调节转运体GLUT4的基因在心脏的表达减弱。然而，类似的代谢逆调节是否发生在非心肌中还没有得到评估。此外，这种代谢调节反应涉及的机制尚不清楚。我们假设，骨骼肌PPARa基因调控通路的激活，如在糖尿病状态下发生的，其下游对脂肪酸的利用和能量产生的影响导致GLUT4基因转录的特异性变化，从而减少骨骼肌对葡萄糖的摄取。鉴于PPARa被脂肪酸激活，GLUT4基因表达的这种变化可能与胰岛素抵抗的发展有关，已知的胰岛素抵抗发生在高脂血症的背景下。这项建议旨在[1]描述GLUT4启动子的PPARa反应区域(S)，[2]鉴定和表征参与PPARa介导的GLUT4基因转录抑制的反式作用因子和上游信号事件，以及[3]表征骨骼肌特异性PPARa高表达转基因小鼠(MLC-PPAR小鼠)的代谢表型。因此，这些研究将有助于剖析PPARa激活后GLUT4表达下调所涉及的分子调控机制，并确定骨骼肌PPARa途径的结构性激活是否会导致体内葡萄糖利用和胰岛素抵抗的改变。这些研究的长期目标是增加我们对脂代谢变化和糖尿病发展之间联系的了解，并确定与胰岛素抵抗和糖尿病治疗相关的新治疗干预措施的潜在靶点。

DESCRIPTION (provided by applicant): Evidence is emerging that lipid metabolic derangements play a significant role in the development of insulin resistance and diabetes mellitus. Specifically, high levels of circulating fatty acids impinge upon the capacity of skeletal muscle to import and utilize glucose. Recent work suggests that the nuclear receptor transcription factor, peroxisome proliferator-activated receptor a (PPARa), is activated in the diabetic heart leading to counter-regulation of glucose transport and utilization, including diminished cardiac expression of the gene encoding the insulin-regulated transporter, GLUT4. However, whether similar metabolic counter-regulation occurs in non-cardiac muscle has not yet been evaluated. Moreover, the mechanisms involved in this metabolic regulatory response are unknown. We hypothesize that activation of the skeletal muscle PPARa gene regulatory pathway, such as occurs in the diabetic state, and its downstream effects on fatty acid utilization and energy production lead to specific alterations in GLUT4 gene transcription and consequently, diminished glucose uptake in skeletal muscle. This alteration in GLUT4 gene expression could be involved in the development of insulin resistance known to occur in the context of hyperlipidemic states given that PPARa is activated by fatty acids. This proposal is designed to [1] delineate the PPARa-responsive region(s) of the GLUT4 promoter, [2] identify and characterize the trans-acting factors and upstream signaling events involved in the PPARa-mediated transcriptional repression of the GLUT4 gene, and [3] characterize the metabolic phenotype of transgenic mice with skeletal muscle-specific overexpression of PPARa (MLC-PPAR mice). Accordingly, these studies will serve to dissect the molecular regulatory mechanisms involved in the down-regulation of GLUT4 expression following PPARa activation and determine whether constitutive activation of the skeletal muscle PPARa pathway leads to alterations in glucose utilization and insulin resistance in vivo. The long-term goals of these studies are to increase our understanding of the link between alterations in lipid metabolism and the development of diabetes and to identify potential targets of novel therapeutic interventions relevant to the treatment of insulin resistance and diabetes.