Role of Dietary Nutrients in Induction of Pseudocapillarization and the Functional Consequences for Hyperlipidemia

摘要 这项提议的中心原则是，现代饮食因食物而增加了膳食营养。 准备技术和饮食营养素的变化导致了一个多年的过程 这就是所谓的假毛细血管化。假性毛细血管形成是肝脏的一种超微结构改变 窦状内皮细胞(LSECs)，见于衰老实验动物和人类 早在生命的第四个十年就开始了。假性毛细血管LSEC也表现出功能变化， 特别是它们吞噬某些底物的能力。伪毛细管化已经与 对他汀类药物治疗有部分反应或无反应的血脂变化 导致所谓的动脉粥样硬化的残余风险(即不能用他汀类药物治疗)。 这个应用程序的总体目标是了解连接饮食的机制 增强衰老过程中LSECs的形态和功能变化，以确定其影响 这些变化对高脂血症的影响，并确定是否有逆转老龄的治疗策略 LSec表型可能对临床有益。 具体目标：目标1将研究将饮食变化与信号联系起来的可能途径 下调LSECs中的一氧化氮途径，以确定导致 假毛细血管化。目标2将使用尖端方法论重新审视 乳糜管残留物清除；将研究老年患者逆转假性毛细血管形成的方法 或加重大鼠LSECs的变化，并检测其对餐后血脂、血脂的影响 LSECs清除、LSEC内吞作用和超微结构；并将检查内吞机制 参与青年大鼠、老年大鼠和老年大鼠LSECs的脂质清除 假毛细血管化。

ABSTRACT The central tenet of this proposal is that the modern diet is enhanced in dietary nutrients due to food preparation techniques and a shift in dietary nutrients that leads over many years leads to a process called pseudocapillarization. Pseudocapillarization is defined as an ultrastructural change of liver sinusoidal endothelial cells (LSECs) that is seen in aging experimental animals and also in humans starting as early as the 4th decade of life. Pseudocapillarized LSECs also demonstrate functional changes, specifically in their ability to endocytose certain substrates. Pseudocapillarization has been linked to changes in serum lipids that are partially responsive or unresponsive to statin therapy and therefore contribute to the so-called residual risk for atherosclerosis (i.e. not treatable with statins). The overall objectives of this application are to understand the mechanisms that link dietary enhancements to morphological and functional changes seen in LSECs in aging, to establish the impact of these changes on hyperlipidemia, and to determine whether therapeutic strategies to reverse the aged LSEC phenotype might be clinically beneficial. Specific aims: aim 1 will examine possible pathways that link dietary changes to signaling that downregulates the nitric oxide pathway in LSECs to determine the aberrant signaling that leads to pseudocapillarization. Aim 2 will use cutting-edge methodology to re-examine the mechanism of chylomicron remnant clearance; will examine approaches to either reverse pseudocapillarization in aged rats or exacerbate the change in LSECs and examine the effect on post-prandial lipid profiles, lipid clearance by LSECs, LSEC endocytosis and ultrastructure; and will examine the endocytotic machinery involved in lipid clearance in LSECs from young rats, old rats and old rats with reversal of pseudocapillarization.