dc.contributor.author
Pandey, Vikash
dc.contributor.author
Sultan, Marc
dc.contributor.author
Kashofer, Karl
dc.contributor.author
Ralser, Meryem
dc.contributor.author
Amstislavskiy, Vyacheslav
dc.contributor.author
Starmann, Julia
dc.contributor.author
Osprian, Ingrid
dc.contributor.author
Grimm, Christina
dc.contributor.author
Hache, Hendrik
dc.contributor.author
Yaspo, Marie-Laure
dc.contributor.author
Sültmann, Holger
dc.contributor.author
Trauner, Michael
dc.contributor.author
Denk, Helmut
dc.contributor.author
Zatloukal, Kurt
dc.contributor.author
Lehrach, Hans
dc.contributor.author
Wierling, Christoph
dc.date.accessioned
2018-06-08T03:24:40Z
dc.date.available
2015-02-19T13:20:26.632Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/15109
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-19297
dc.description.abstract
Background Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of
disease states ranging from mild steatosis characterized by an abnormal
retention of lipids within liver cells to steatohepatitis (NASH) showing fat
accumulation, inflammation, ballooning and degradation of hepatocytes, and
fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and
hepatocellular carcinoma. Methodology and Results In this study we have
analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show
different degrees of steatohepatitis when administered a
3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC) containing diet. RNA-Seq gene
expression analysis, protein analysis and metabolic profiling were applied to
identify differentially expressed genes/proteins and perturbed metabolite
levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed
alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism
upon other pathways. To understand metabolic changes of arachidonic acid
metabolism in the light of disease expression profiles a kinetic model of this
pathway was developed and optimized according to metabolite levels.
Subsequently, the model was used to study in silico effects of potential drug
targets for steatohepatitis. Conclusions We identified AA/eicosanoid
metabolism as highly perturbed in DDC-induced mice using a combination of an
experimental and in silico approach. Our analysis of the AA/eicosanoid
metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE),
15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are
perturbed in DDC mice. We further demonstrate that a dynamic model can be used
for qualitative prediction of metabolic changes based on transcriptomics data
in a disease-related context. Furthermore, SAMe metabolism was identified as
being perturbed due to DDC treatment. Several genes as well as some
metabolites of this module show differences between A/J and C57BL/6J on the
one hand and PWD/PhJ on the other.
en
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-
Treated Mouse Strains
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
PLoS ONE. - 9 (2014), 10, Artikel Nr. e111006
dcterms.bibliographicCitation.doi
10.1371/journal.pone.0111006
dcterms.bibliographicCitation.url
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111006
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDOCS_document_000000021885
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000004567
dcterms.accessRights.openaire
open access