Molecular Mechanisms of Mitigation of Insulin Induction of SREBP-1c by N-3 PUFA

描述(由申请人提供)： 了解在慢性高胰岛素血症状态下SREBP-1c及其下游成脂酶靶点的慢性异常调节的机制一直是我们实验室的研究重点。具体地说，我们一直在研究大鼠SREBP-1c启动子的胰岛素响应顺式作用元件，并发现其完整的反应需要与LXR1、NF-Y、Sp1和SREBP-1c本身结合的多个顺式作用位点的参与。作为我们正在进行的研究的合乎逻辑的扩展，我们现在建议研究多不饱和脂肪酸(PUFA)，特别是n-3PUFA减少SREBP-1c转录的分子机制，从而有效地减轻胰岛素诱导高胰岛素状态下的造脂酶表达和肝脂过量产生的影响。为了系统地研究n-3PUFA减轻SREBP-1c基因表达诱导的细胞和分子机制，我们提出了一个三管齐下的假说：(I)n-3PUFA调控LXR1与转录因子(Sp1，SREBP-1c)、共激活因子(SRC-1，CBP)和共抑制因子(NCoR，SMRT，HDAC)的相互作用，(Ii)n-3PUFA改变LXR1内源性配体的结合和/或代谢，以及(Iii)由胰岛素和PUFA调节SREBP-1c启动子的核因子及其翻译后修饰仍有待定义。对退伍军人医疗保健的潜在影响：在退伍军人医疗保健系统中接受医疗保健的退伍军人中，肥胖症和II型糖尿病的患病率非常高。伴随这些疾病的血脂异常是动脉粥样硬化性血管疾病的重要危险因素，动脉粥样硬化性血管疾病在退伍军人中也非常普遍。在退伍军人群体中，肥胖和II型糖尿病的血管并发症的综合影响导致了退伍军人的显著发病率和死亡率。此外，提供与这些并发症相关的护理需要退伍军人保健系统的巨额费用。需要有效的治疗方法来治疗肥胖、II型糖尿病和代谢综合征，主要是高甘油三酯血症和低高密度脂蛋白血症。这项研究将为开发新的、有效的治疗方法提供必要的信息。

DESCRIPTION (provided by applicant): Understanding the mechanistic basis of chronic aberrant regulation of SREBP-1c and its downstream lipogenic enzyme targets in chronic hyperinsulinemic states has been a focus of research in our laboratory. Specifically, we have been studying the insulin-responsive cis-acting elements of the rat SREBP-1c promoter and have found that its full response requires participation of multiple cis-acting sites that bind to LXR1, NF-Y, Sp1 and SREBP-1c itself. As a logical extension of our ongoing studies we now propose to examine the molecular mechanisms by which polyunsaturated fatty acids (PUFA), specifically n-3 PUFA, reduce transcription of SREBP-1c, thereby effectively mitigating the effect of insulin to induce lipogenic enzyme expression and hepatic lipid overproduction in hyperinsulinemic states. To systematically examine the cellular and molecular mechanisms by which n-3 PUFA mitigate induction of SREBP-1c gene expression we propose a three- pronged hypothesis: (i) n-3 PUFA modulate the interaction of LXR1 with transcription factors (Sp1, SREBP- 1c), co-activators (SRC-1, CBP), and co-repressors (NcoR, SMRT, HDAC), (ii) n-3 PUFA alter binding and/or metabolism of endogenous ligands of LXR1 and (iii) the full complement of nuclear factors and their posttranslational modifications that modulate SREBP-1c promoter by insulin and PUFA remain to be defined. POTENTIAL IMPACT ON VETERAN'S HEALTH CARE: The prevalence of obesity and Type II Diabetes is extraordinarily high among veterans receiving health care within the VA Health Care System. The dyslipidemia that accompanies these disorders is a significant risk factor for atherosclerotic vascular disease which is also highly prevalent in the VA population. The combined effects of vascular complications of obesity and Type II Diabetes in the Veteran population results in significant morbidity and mortality among Veterans. Further, providing care related to these complications entails significant cost to the VA Health Care System. Effective treatment modalities for the dyslipidemia that accompanies obesity, Type II Diabetes, and Metabolic Syndrome, primarily hypertriglyceridemia and low HDLC, are needed. Research such as the proposed studies that examines the molecular mechanisms underlying dyslipidemia in hyperinsulinemic states will provide needed information for development of new, effective treatments.