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Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice
Author(s) -
Busch Clara JanaLui,
Hendrikx Tim,
Weismann David,
Jäckel Sven,
Walenbergh Sofie M.A.,
Rendeiro André F.,
Weißer Juliane,
Puhm Florian,
Hladik Anastasiya,
Göderle Laura,
PapacMilicevic Nikolina,
Haas Gerald,
Millischer Vincent,
Subramaniam Saravanan,
Knapp Sylvia,
Bennett Keiryn L.,
Bock Christoph,
Reinhardt Christoph,
ShiriSverdlov Ronit,
Binder Christoph J.
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28970
Subject(s) - scavenger receptor , inflammation , malondialdehyde , oxidative stress , epitope , biology , immunology , in vivo , cd36 , cytokine , lipid peroxidation , lipoprotein , receptor , medicine , antibody , endocrinology , biochemistry , cholesterol , microbiology and biotechnology
Diet‐related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet‐induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low‐density lipoprotein receptor‐deficient mice on a Western‐type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo . MDA‐induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low‐density lipoprotein receptor‐deficient mice on a Western‐type diet. Conclusion : Accumulation of MDA epitopes plays a major role during diet‐induced hepatic inflammation and can be ameliorated by administration of an anti‐MDA antibody. (H epatology 2017;65:1181‐1195)