Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System.
Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System.
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DOI：
10.1016/j.jcmgh.2020.09.007
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发表时间：
2021
影响因子：
7.2
通讯作者：
Jirón Tamburini BA
中科院分区：
文献类型：
--
作者：
Burchill MA;Finlon JM;Goldberg AR;Gillen AE;Dahms PA;McMahan RH;Tye A;Winter AB;Reisz JA;Bohrnsen E;Schafer JB;D'Alessandro A;Orlicky DJ;Kriss MS;Rosen HR;McCullough RL;Jirón Tamburini BA
随着非酒精性脂肪性肝炎 (NASH) 的发病率持续上升，在开发可降低发病率和死亡率的新疗法之前，需要了解疾病期间正常肝功能如何受到影响。然而，人们对淋巴管系统从肝脏运输蛋白质和细胞如何受到炎症介质或疾病期间的影响知之甚少。为了回答这些问题，我们利用了经过充分验证的 NASH 小鼠模型，并暴露于高度氧化的低密度脂蛋白 (oxLDL)。除了单细胞测序、多重免疫荧光和肝淋巴内皮细胞 (LEC) 代谢组学分析外，我们还评估了体外和体内的淋巴通透性和转运。我们证实了 NASH 中人类和小鼠肝脏淋巴脉管系统的相似性，我们发现淋巴脉管系统随着疾病的进展而扩张，并导致对淋巴特性和功能重要的基因下调。我们还证明，在患有 NASH 的小鼠中，肝内注射后，异硫氰酸荧光素 (FITC) 右旋糖酐不会在肝脏引流淋巴结中积聚，这一缺陷通过淋巴生长因子、重组血管内皮生长因子 C (rVEGFC) 的治疗性给药而得到修复。同样，暴露于 oxLDL 会减少门静脉引流淋巴结中以及通过 LEC 单层的 FITC-葡聚糖的量。我们提供的证据表明，oxLDL 影响淋巴通透性的机制是通过降低 Prox1 表达，从而降低淋巴特异性基因表达，阻碍 LEC 代谢并重组高渗透性淋巴细胞-细胞连接，这是毛细淋巴管的一个决定性特征。我们认为 oxLDL 是导致肝脏淋巴通透性降低的主要因素，这种变化与慢性肝病期间蛋白质稳态降低和炎症增加一致。
As the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease. To answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo. Confirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries. We identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.
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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
影响因子：
20.3
作者：
Amatschek, Stefan;Kriehuber, Ernst;Maurer, Dieter
通讯作者：
Maurer, Dieter
DOI：
10.5395/rde.2016.41.1.74
发表时间：
2016-02
期刊：
Restorative dentistry & endodontics
影响因子：
--
作者：
Kim HY
通讯作者：
Kim HY
影响因子：
9
作者：
DUMONT, AE;MULHOLLAND, JH
通讯作者：
MULHOLLAND, JH
影响因子：
15.9
作者：
Lanaspa, Miguel A.;Andres-Hernando, Ana;Tolan, Dean R.
通讯作者：
Tolan, Dean R.