Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic- but not liver sinusoidal-endothelial cells via VEGFR-3 regulation of VE-Cadherin.
Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic- but not liver sinusoidal-endothelial cells via VEGFR-3 regulation of VE-Cadherin.
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DOI：
10.3389/fphys.2022.1021038
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发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
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肝脏的淋巴管系统对肝功能至关重要，因为它维持液体和蛋白质稳态，并且对于免疫细胞转运到淋巴结很重要。慢性肝病与炎症介质包括氧化低密度脂蛋白（oxLDL）的表达增加有关。非酒精性脂肪性肝病（NAFLD）、慢性丙型肝炎感染（HCV）、酒精相关性肝病（ALD）和胆汁淤积性肝病的肝内oxLDL水平升高。为了确定在慢性肝病中肝淋巴功能是否受损，其中已经记录了oxLDL增加，我们测量了NAFLD、ALD和原发性硬化性胆管炎（PSC）小鼠模型中的肝淋巴功能。我们发现，Mdr 2 −/−（PSC）、Lieber-DeCarli乙醇喂养（ALD）和高脂肪和高胆固醇饮食喂养（NAFLD）小鼠将FITC标记的葡聚糖从肝实质运输到肝引流淋巴结的能力均显著受损。利用体外渗透性测定，我们发现oxLDL降低淋巴管内皮细胞（LEC）的渗透性，但不是肝窦内皮细胞（LSEC）的。在这里，我们证明，LEC和LSEC差异调节SRC家族激酶，MAPK激酶和VE钙粘蛋白在响应oxLDL。此外，血管内皮生长因子（VEGF）C或D（VEGFR-3配体）似乎调节VE-钙粘蛋白的表达，以及在体外和体内oxLDL处理后降低LEC的细胞通透性。这些发现表明oxLDL通过收紧细胞-细胞连接来阻碍蛋白质通过血管的转运。重要的是，VEGFR-3通过其配体的结合防止VE-钙粘蛋白上调并改善淋巴渗透性。这些研究为恢复肝淋巴功能和改善肝功能提供了潜在的治疗靶点。
The lymphatic vasculature of the liver is vital for liver function as it maintains fluid and protein homeostasis and is important for immune cell transport to the lymph node. Chronic liver disease is associated with increased expression of inflammatory mediators including oxidized low-density lipoprotein (oxLDL). Intrahepatic levels of oxLDL are elevated in nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C infection (HCV), alcohol-associated liver disease (ALD), and cholestatic liver diseases. To determine if liver lymphatic function is impaired in chronic liver diseases, in which increased oxLDL has been documented, we measured liver lymphatic function in murine models of NAFLD, ALD and primary sclerosing cholangitis (PSC). We found that Mdr2−/− (PSC), Lieber-DeCarli ethanol fed (ALD) and high fat and high cholesterol diet fed (NAFLD) mice all had a significant impairment in the ability to traffic FITC labeled dextran from the liver parenchyma to the liver draining lymph nodes. Utilizing an in vitro permeability assay, we found that oxLDL decreased the permeability of lymphatic endothelial cells (LEC)s, but not liver sinusoidal endothelial cells (LSEC)s. Here we demonstrate that LECs and LSECs differentially regulate SRC-family kinases, MAPK kinase and VE-Cadherin in response to oxLDL. Furthermore, Vascular Endothelial Growth Factor (VEGF)C or D (VEGFR-3 ligands) appear to regulate VE-Cadherin expression as well as decrease cellular permeability of LECs in vitro and in vivo after oxLDL treatment. These findings suggest that oxLDL acts to impede protein transport through the lymphatics through tightening of the cell-cell junctions. Importantly, engagement of VEGFR-3 by its ligands prevents VE-Cadherin upregulation and improves lymphatic permeability. These studies provide a potential therapeutic target to restore liver lymphatic function and improve liver function.
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氧化的低密度脂蛋白积累与实验性胆汁淤积中的肝纤维化有关。
DOI：
10.1590/s1807-59322008000400020
发表时间：
2008-08
期刊：
Clinics (Sao Paulo, Brazil)
影响因子：
--
作者：
Karadeniz G;Acikgoz S;Tekin IO;Tascýlar O;Gun BD;Cömert M
通讯作者：
Cömert M
DOI：
10.1016/j.jcmgh.2022.07.007
发表时间：
2022
影响因子：
7.2
作者：
Ceci, Ludovica;Chen, Lixian;Baiocchi, Leonardo;Wu, Nan;Kennedy, Lindsey;Carpino, Guido;Kyritsi, Konstantina;Zhou, Tianhao;Owen, Travis;Kundu, Debjyoti;Sybenga, Amelia;Isidan, Abdulkadir;Ekser, Burcin;Franchitto, Antonio;Onori, Paolo;Gaudio, Eugenio;Mancinelli, Romina;Francis, Heather;Alpini, Gianfranco;Glaser, Shannon
通讯作者：
Glaser, Shannon
影响因子：
9
作者：
DUMONT, AE;MULHOLLAND, JH
通讯作者：
MULHOLLAND, JH
影响因子：
0.8
作者：
Aboismail, Ashraf;El-Shazly, Mohamed;Abo-Yossef, Rania
通讯作者：
Abo-Yossef, Rania
影响因子：
15.8
作者：
Maneechotesuwan K;Yao X;Ito K;Jazrawi E;Usmani OS;Adcock IM;Barnes PJ
通讯作者：
Barnes PJ