Department of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
PLoS One. 2014 Dec 26;9(12):e115005. doi: 10.1371/journal.pone.0115005. eCollection 2014.
Liver sinusoidal endothelial cells (LSEC) are characterized by the presence of fenestrations that are not bridged by a diaphragm. The molecular mechanisms that control the formation of the fenestrations are largely unclear. Here we report that mice, which are deficient in plasmalemma vesicle-associated protein (PLVAP), develop a distinct phenotype that is caused by the lack of sinusoidal fenestrations. Fenestrations with a diaphragm were not observed in mouse LSEC at three weeks of age, but were present during embryonic life starting from embryonic day 12.5. PLVAP was expressed in LSEC of wild-type mice, but not in that of Plvap-deficient littermates. Plvap(-/-) LSEC showed a pronounced and highly significant reduction in the number of fenestrations, a finding, which was seen both by transmission and scanning electron microscopy. The lack of fenestrations was associated with an impaired passage of macromolecules such as FITC-dextran and quantum dot nanoparticles from the sinusoidal lumen into Disse's space. Plvap-deficient mice suffered from a pronounced hyperlipoproteinemia as evidenced by milky plasma and the presence of lipid granules that occluded kidney and liver capillaries. By NMR spectroscopy of plasma, the nature of hyperlipoproteinemia was identified as massive accumulation of chylomicron remnants. Plasma levels of low density lipoproteins (LDL) were also significantly increased as were those of cholesterol and triglycerides. In contrast, plasma levels of high density lipoproteins (HDL), albumin and total protein were reduced. At around three weeks of life, Plvap-deficient livers developed extensive multivesicular steatosis, steatohepatitis, and fibrosis. PLVAP is critically required for the formation of fenestrations in LSEC. Lack of fenestrations caused by PLVAP deficiency substantially impairs the passage of chylomicron remnants between liver sinusoids and hepatocytes, and finally leads to liver damage.
肝窦内皮细胞（LSEC）的特征是存在窗孔，这些窗孔没有被隔膜桥接。控制窗孔形成的分子机制在很大程度上尚不清楚。在这里，我们报告说，缺乏质膜小泡相关蛋白（PLVAP）的小鼠表现出明显的表型，这是由于缺乏窦状隙窗孔所致。在三周龄的小鼠 LSEC 中未观察到具有隔膜的窗孔，但在从胚胎第 12.5 天开始的胚胎生命中存在。野生型小鼠的 LSEC 表达 PLVAP，但 Plvap 缺陷型同窝仔鼠中则没有。Plvap(-/-)LSEC 的窗孔数量明显减少，而且在透射和扫描电子显微镜下都可以看到这一发现。缺乏窗孔与大分子如 FITC-葡聚糖和量子点纳米颗粒从窦状腔进入 Disse 空间的通透性受损有关。Plvap 缺陷型小鼠表现出明显的高脂蛋白血症，表现为乳糜血浆和脂质颗粒阻塞肾脏和肝脏毛细血管，这是显而易见的。通过对血浆的 NMR 光谱分析，确定了高脂蛋白血症的性质是大量乳糜微粒残基的积累。低密度脂蛋白（LDL）的血浆水平也显著增加，胆固醇和甘油三酯的水平也是如此。相反，高密度脂蛋白（HDL）、白蛋白和总蛋白的血浆水平降低。在大约三周大时，Plvap 缺陷型肝脏发生广泛的多泡性脂肪变性、脂肪性肝炎和纤维化。PLVAP 对于 LSEC 中窗孔的形成至关重要。PLVAP 缺乏导致的窗孔缺失会严重损害乳糜微粒残基在肝窦和肝细胞之间的通过，最终导致肝损伤。
