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

了解脂蛋白代谢对预防血管疾病至关重要。肝脏是脂蛋白代谢的主要场所。肝脏代谢脂蛋白的第一步是将脂蛋白从血液通过肝窦内皮细胞转移到肝细胞。窦状隙内皮细胞含有称为窗孔的孔，其被认为允许大物质直接通过，从而基于大小过滤脂蛋白。我们建议充分定义的作用，在超滤的微粒，如脂蛋白和微球的窗孔。这将证实，肝内皮中的窗孔超滤是一种重要的生物学过程，类似于肾脏的过滤，与脂蛋白代谢相关。我们将确定是否氧化应激，产生大的差距，在窦内皮细胞，增加转移到肝脏的脂蛋白。这为脂肪肝提供了一种新的机制，即中毒性肝损伤，因此，这是这种疾病的治疗靶点。我们将确定合成的非离子表面活性剂普朗尼克407诱导的窗孔损失是否会减少脂蛋白的转移。这是一个全新的机制和危险因素的红细胞血症。最后，我们将研究脂蛋白（a），它是血管疾病的潜在危险因素。我们将评估脂蛋白（a），通过结合其他脂蛋白并增加其大小，阻碍其通过开窗进行后续肝脏代谢。从基础的角度来看，这些研究将证明肝内皮细胞中的开窗是一个超滤系统，对脂蛋白代谢有重要意义。从临床角度来看，这些研究将产生脂蛋白肝脏代谢受损的新机制，并表明窗孔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.