Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system.,Cellular and Molecular Gastroenterology and Hepatology

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Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-09-19 , DOI: 10.1016/j.jcmgh.2020.09.007
Matthew A Burchill ₁ , Jeffrey M Finlon ₂ , Alyssa R Goldberg ₃ , Austin E Gillen ₄ , Petra A Dahms ₂ , Rachel H McMahan ₅ , Anne Tye ₂ , Andrew B Winter ₆ , Julie A Reisz ₇ , Eric Bohrnsen ₇ , Johnathon B Schafer ₂ , Angelo D'Alessandro ₇ , David J Orlicky ₈ , Michael S Kriss ₂ , Hugo R Rosen ₉ , Rebecca L McCullough ₆ , Beth A Jirón Tamburini ₁₀

Affiliation

Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; RNA Biosciences Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
RNA Biosciences Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
University of Southern California Keck School of Medicine, Los Angeles, California.
Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; RNA Biosciences Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Background and Aims

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.

Methods

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.

Results

Confirming similarities between human and mouse 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 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, rVEGFC. Similarly, exposure to oxLDL also 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 the highly permeable lymphatic cell-cell junctions characteristic of lymphatic capillaries.

Conclusions

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.

中文翻译：

氧化低密度脂蛋白会导致肝脏淋巴系统功能障碍。

背景和目标

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。

方法

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) 的代谢组学分析外，我们还评估了体外和体内的淋巴通透性和转运。

结果

我们证实了 NASH 中人和小鼠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，并导致对淋巴管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 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 rVEGFC 的治疗性给药得以挽救。同样，暴露于 oxLDL 也减少了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表达来降低淋巴特异性基因表达、阻碍 LEC 代谢以及毛细淋巴管的高渗透性淋巴细胞-细胞连接特征。