Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State

摘要： 糖尿病患者的主要死因是心血管疾病(CVD)。我们的 长期目标是确定预防糖尿病心血管疾病的新治疗靶点 病人。在上一个资助周期中，我们鉴定了含有黄素的酶 单加氧酶3(FMO3)是糖尿病相关心血管疾病的潜在介质 疾病。肥胖/糖尿病患者肝脏中Fmo3被胰岛素抑制而增加 此外，Fmo3基因的敲除完全阻止了 胰岛素抵抗小鼠的高血糖、高脂血症和动脉粥样硬化。FMO3 通路是令人兴奋的，因为在胰岛素中观察到的效应是惊人的 耐药小鼠，以及早期研究表明Fmo3也在 患有糖尿病的人类。此外，FMO3是通过无偏倚方式确定的 方法表明，它可能是一条中央通路，直到现在才被发现 已有适当的工具可用。这项提案的总体目标是定义 糖尿病/FMO3/动脉粥样硬化途径中的机制联系，重点是 转录因子，固醇调节元件结合蛋白(SREBP)-2。 已确定为FMO3 S行动的调解人。我们的目标是：(1) 确定胰岛素和糖尿病如何调节FMO3；(2)定义产品或靶点 下游作用所需的FMO3酶；以及(3)通过以下方式定义该机制 其中FMO3改变胆固醇代谢以诱导SREBP-2。我们预计这些 研究将提供必要的机制细节，以确定FMO3是否以及如何 通路可以被操控用于治疗。

Abstract: The leading cause of death in diabetic patients is cardiovascular disease (CVD). Our long-term goal is to identify new therapeutic targets for the prevention of CVD in diabetic patients. In the last grant cycle, we identified the enzyme, flavin-containing monooxygenase 3 (FMO3) as a potential mediator of diabetes associated cardiovascular disease. FMO3 is suppressed by insulin and increased in the livers of obese/diabetic subjects; moreover, knockdown of FMO3 completely prevented the development of hyperglycemia, hyperlipidemia and atherosclerosis in insulin resistant mice. The FMO3 pathway is exciting because of the striking magnitude of the effects observed in insulin resistant mice and the fact that early studies suggest that FMO3 is also dysregulated in diabetic humans. Moreover, the fact that FMO3 was identified via non-biased approaches suggests that it may be a central pathway discovered only now that the proper tools have become available. The overall goal of this proposal is to define the mechanistic links in the diabetes/FMO3/atherosclerosis pathway, focusing on the transcription factor, Sterol Regulatory Element Binding Protein (SREBP)-2, which we have identified as a mediator of FMO3's actions. Our aims are as follows: (1) determine how insulin and diabetes regulate FMO3; (2) define the product or target of the FMO3 enzyme required for its downstream effects; and (3) define the mechanism by which FMO3 alters cholesterol metabolism to induce SREBP-2. We expect that these studies will provide the mechanistic detail necessary to determine if and how the FMO3 pathway can be manipulated for therapeutic use.