How is lipoprotein disposition influenced by fenestrae in the hepatic sinusoidal endothelium?

了解脂蛋白代谢对于预防血管疾病至关重要。肝脏是脂蛋白代谢的主要部位。肝脏代谢脂蛋白的第一步是它们通过肝窦内皮细胞从血液转移到肝细胞。肝窦内皮细胞含有被称为窗孔的小孔，人们认为这些小孔允许大物质直接通过，从而根据大小过滤脂蛋白。我们建议充分定义Fenestrae在脂蛋白和微球等颗粒超滤中的作用。这将证实，肝内皮细胞的窗孔超滤是一个类似于肾滤过的重要生物学过程，与脂蛋白代谢有关。我们将确定氧化应激是否增加了脂蛋白向肝脏的转移，氧化应激在肝窦内皮细胞中产生了巨大的间隙。这为中毒性肝损伤后脂肪肝提供了一种新的机制，从而成为这种情况的治疗靶点。我们将确定合成的非离子表面活性剂Pluronic 407引起的窗孔损失是否会减少脂蛋白的转移。这是一种全新的高脂血症发病机制和危险因素。最后，我们将研究脂蛋白(A)，它是血管疾病的一个潜在风险因素。我们将用脂蛋白(A)来评估，通过结合其他脂蛋白并增加它们的大小，阻碍它们通过窗口转移到随后的肝脏代谢。从基础的角度来看，这些研究将证明，肝内皮细胞的开窗是一个对脂蛋白代谢具有重要意义的超滤系统。从临床角度来看，这些研究将为肝脏脂蛋白代谢受损提供新的机制，并表明Fenestrae是开发降脂药物治疗的潜在靶点。

Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully define the role of fenestrae in the ultrafiltration of particles such as lipoproteins and microspheres. This will confirm that ultrafiltration by fenestrae in the liver endothelium is an important biological process akin to filtration by the kidney, and relevant for lipoprotein metabolism. We will determine whether oxidative stress, which generates large gaps in the sinusoidal endothelium, increases the transfer of lipoproteins into the liver. This provides a novel mechanism for fatty liver that follows toxic liver injury, and hence, a therapeutic target for this condition. We will determine whether loss of fenestrae induced by the synthetic non-ionic surfactant, pluronic 407, reduces transfer of lipoproteins. This is an entirely novel mechanism and risk factor for hyperlipidaemia. Finally we will investigate lipoprotein (a) which is a potent risk factor for vascular disease. We will assess with lipoprotein (a), through binding other lipoproteins and increasing their size, impedes their transfer through the fenestrations for subsequent hepatic metabolism. From the basic perspective, these studies will prove that fenestrations in the liver endothelial cell are an ultrafiltration system that is significant for lipoprotein metabolism. From the clinical perspective, the studies will generate novel mechanisms for impaired hepatic metabolism of lipoproteins as well as indicating that fenestrae are a potential target for the development of lipid-lowering pharmacotherapies.