Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage.
Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage.
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DOI：
10.1371/journal.pone.0115005
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tamm ER
中科院分区：
文献类型：
--
作者：
Herrnberger L;Hennig R;Kremer W;Hellerbrand C;Goepferich A;Kalbitzer HR;Tamm ER
肝窦内皮细胞 (LSEC) 的特征是存在未通过隔膜桥接的开窗。控制开窗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，缺乏质膜囊泡相关蛋白（PLVAP）的小鼠会形成一种独特的表型，这是由于缺乏正弦开窗引起的。三周龄的小鼠 LSEC 中没有观察到带有隔膜的开窗，但从胚胎第 12.5 天开始的胚胎生命期间就存在。 PLVAP 在野生型小鼠的 LSEC 中表达，但在 Plvap 缺陷的同窝小鼠中不表达。 Plvap-/- LSEC 显示出开窗数量显着且非常显着的减少，这一发现通过透射电子显微镜和扫描电子显微镜都可以看到。缺乏开窗与大分子（例如 FITC-葡聚糖和量子点纳米粒子）从正弦腔进入迪斯空间的通道受损有关。 Plvap 缺陷小鼠患有明显的高脂蛋白血症，表现为乳白色血浆和阻塞肾和肝毛细血管的脂质颗粒的存在。通过血浆核磁共振波谱，高脂蛋白血症的本质被确定为乳糜微粒残留物的大量积累。低密度脂蛋白（LDL）的血浆水平以及胆固醇和甘油三酯的水平也显着增加。相反，血浆中高密度脂蛋白（HDL）、白蛋白和总蛋白的水平降低。在出生后三周左右，Plvap 缺陷的肝脏出现广泛的多泡性脂肪变性、脂肪性肝炎和纤维化。 PLVAP 对于 LSEC 开窗的形成至关重要。 PLVAP缺乏导致的开窗缺失严重损害了乳糜微粒残余物在肝窦和肝细胞之间的通道，最终导致肝脏损伤。
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.
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影响因子：
4.2
作者：
Cohen DE;Fisher EA
通讯作者：
Fisher EA
影响因子：
3.4
作者：
Herrnberger, Leonie;Ebner, Kathrin;Tamm, Ernst R.
通讯作者：
Tamm, Ernst R.
影响因子：
2.3
作者：
Herrnberger, Leonie;Seitz, Roswitha;Tamm, Ernst R.
通讯作者：
Tamm, Ernst R.
DOI：
10.1073/pnas.0603501103
发表时间：
2006-11-07
影响因子：
11.1
作者：
Ioannidou, Sofia;Deinhardt, Katrin;Shima, David T.
通讯作者：
Shima, David T.
影响因子：
20.3
作者：
Keuschnigg, Johannes;Tvorogov, Denis;Jalkanen, Sirpa
通讯作者：
Jalkanen, Sirpa