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Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System.

Authors
  • Burchill, Matthew A1
  • Finlon, Jeffrey M2
  • Goldberg, Alyssa R3
  • Gillen, Austin E4
  • Dahms, Petra A2
  • McMahan, Rachel H5
  • Tye, Anne2
  • Winter, Andrew B6
  • Reisz, Julie A7
  • Bohrnsen, Eric7
  • Schafer, Johnathon B2
  • D'Alessandro, Angelo7
  • Orlicky, David J8
  • Kriss, Michael S2
  • Rosen, Hugo R9
  • McCullough, Rebecca L6
  • Jirón Tamburini, Beth A10
  • 1 Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; RNA Biosciences Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: [email protected]
  • 2 Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 3 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.
  • 4 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.
  • 5 Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 6 Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 7 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 8 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 9 University of Southern California Keck School of Medicine, Los Angeles, California.
  • 10 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. Electronic address: [email protected]
Type
Published Article
Journal
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier
Publication Date
Jan 01, 2021
Volume
11
Issue
2
Pages
573–595
Identifiers
DOI: 10.1016/j.jcmgh.2020.09.007
PMID: 32961356
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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