Regulation of Endothelial Lipid Metabolism in the Setting of Diabetes and Critical Limb Ischemia to Prevent Surgical Complications

项目摘要 背景与意义： 外周动脉疾病 (PAD) 影响美国 1200 万人（每 27 人中就有 1 人患有外周动脉疾病） 个人）。糖尿病患者进行终末期手术的可能性高出近 10 倍 严重肢体缺血（CLI）和严重下肢截肢等并发症。这导致 手术糖尿病患者承受着巨大的健康、心理和经济负担。因此，它是 为了开发更有效的治疗方法，更好地了解这种慢性疾病的过程至关重要 策略，并改善这些患者的健康。 非诺贝特，一种过氧化物酶体增殖物激活受体 α (PPARα) 激动剂，可降低血清水平 甘油三酯是迄今为止唯一被证明可以降低外周截肢率的药物 糖尿病。然而，目前尚不清楚非诺贝特如何提供这种益处，因此很少用于 有截肢风险的糖尿病和 CLI 外科患者的临床管理。 从头脂肪生成是一种多步骤的脂质合成途径，已知有助于发病机制 糖尿病在非血管器官组织中的发生，并受到脂肪酸合酶（FAS）和 胆碱/乙醇胺磷酸转移酶-1 (CEPT1)。这些酶之间的相互作用可以导致激活 PPARα 介导的信号传导。目前尚不清楚非诺贝特是否会影响从头脂肪生成、内皮细胞 糖尿病背景下细胞（EC）脂质代谢和外周动脉粥样硬化进展。 初步数据：我们观察到非诺贝特确实可以在以下情况下影响外周肢体灌注： 从头改变脂肪生成。我们还观察到 CEPT1 和 FAS 在外周血中含量丰富。 糖尿病和 CLI 患者的动脉内膜。此外，我们最近发现血清循环 患有晚期糖尿病和 CLI 的患者血清中 FAS (cFAS) 升高。此外，cept1敲除 在内皮细胞中，可显着减少动脉粥样硬化进展并使血脂正常化。 创新：该提案的主要目标是确定非诺贝特是否可以从头开始脂肪生成 可以影响糖尿病患者的外周动脉粥样硬化进展。这条调查线将高度 创新，因为它将解决有助于外围的机制中的关键知识差距 糖尿病中的动脉粥样硬化进展，可能有助于为患有这种疾病的外科患者制定治疗方案。 具体目标：我们假设 CEPT1 和 cFAS 是 EC 脂质代谢的关键参与者，并且具有 在糖尿病和 CLI 的情况下外周动脉粥样硬化进展中发挥重要作用。使用补语 结合生化技术和已经生成的小鼠品系，我们将在两个目标中检验这一假设：目标 1 将确定 CEPT1 和 cFAS 是否可以影响外周动脉粥样硬化进展 糖尿病，目标 2 将确定非诺贝特是否影响内皮从头脂肪生成和外周血 动脉粥样硬化进展。

PROJECT ABSTRACT Background & Significance: Peripheral arterial disease (PAD) affects 12 million people in the US (1 in 27 individuals). Individuals with diabetes are nearly 10 times more likely to develop end-stage surgical complications such as critical limb ischemia (CLI) and major lower extremity amputation. This leads to significant health, psychological, and financial burdens on surgical patients with diabetes. Therefore, it is paramount to better understand this chronic disease process in order to develop more effective treatment strategies, and improve the health of these patients. Fenofibrate, a peroxisome proliferator activated receptor alpha (PPARα) agonist that lowers serum triglycerides, is the only medication to date shown to reduce peripheral amputation rates in patients with diabetes. However, it is unknown how Fenofibrate confers this benefit, and therefore it is seldom used in the clinical management of surgical patients with diabetes and CLI who are at risk of amputation. De novo lipogenesis is a multi-step lipid synthesis pathway that is known to contribute to the pathogenesis of diabetes in non-vascular organ tissue, and is regulated by fatty acid synthase (FAS) and choline/ethanolamine phosphotransferase-1 (CEPT1). Interplay between these enzymes can lead to activation of PPARα-mediated signaling. It is unknown whether Fenofibrate can impact de novo lipogenesis, endothelial cell (EC) lipid metabolism, and peripheral arterial atheroprogression in the setting of diabetes. Preliminary Data: We observed that Fenofibrate can indeed affect peripheral limb perfusion in the setting of altered de novo lipogenesis. We also observed that both CEPT1 and FAS are abundant in the peripheral arterial intima of patients with diabetes and CLI. Additionally, we recently discovered that serum circulating FAS (cFAS) is elevated in the serum of patients with advanced diabetes and CLI. Furthermore, cept1 knockout in the endothelium leads to significantly reduced atheroprogression and normalization of serum lipid profiles. Innovation: The main objective of this proposal is to determine whether de novo lipogenesis and Fenofibrate can affect peripheral atheroprogression in the setting of diabetes. This line of investigation will be highly innovative since it will address key knowledge gaps in the mechanisms that contribute to peripheral atheroprogression in diabetes, and may help tailor therapy for surgical patients afflicted by this condition. Specific Aims: We hypothesize that CEPT1 and cFAS are key players in EC lipid metabolism and have important roles in peripheral arterial atheroprogression in the setting of diabetes and CLI. Using a complement of biochemical techniques and already generated mouse lines, we will test this hypothesis in two aims: Aim 1 will determine whether CEPT1 and cFAS can affect peripheral arterial atheroprogression in the setting of diabetes, and Aim 2 will determine whether Fenofibrate affects endothelial de novo lipogenesis and peripheral atheroprogression.