Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State

摘要： 糖尿病患者死亡的主要原因是心血管疾病（CVD）。我们 长期目标是确定预防糖尿病患者CVD的新治疗靶点， 患者在上一个资助周期中，我们发现了一种酶， 单加氧酶3（FMO 3）作为糖尿病相关心血管疾病的潜在介质 疾病FMO 3受胰岛素抑制，在肥胖/糖尿病患者的肝脏中增加 此外，FMO 3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 由于在胰岛素中观察到的效应的惊人幅度， 早期研究表明，FMO 3在小鼠中也存在失调， 糖尿病患者此外，FMO 3是通过无偏倚的 研究方法表明，这可能是一个中心途径，直到现在才发现， 适当的工具已经出现。本提案的总体目标是确定 糖尿病/FMO 3/动脉粥样硬化途径中的机制联系，重点关注 转录因子，固醇调节元件结合蛋白（SREBP）-2，我们 被认为是FMO 3行动的媒介。我们的目标如下：（1） 确定胰岛素和糖尿病如何调节FMO 3;（2）定义胰岛素的产物或靶点。 下游效应所需的FMO 3酶;以及（3）通过以下方式定义机制： FMO 3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，以确定是否以及如何FMO 3 可以操纵该途径用于治疗用途。

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.