dc.contributor.author
Abshagen, Kerstin
dc.contributor.author
König, Matthias
dc.contributor.author
Hoppe, Andreas
dc.contributor.author
Müller, Isabell
dc.contributor.author
Ebert, Matthias
dc.contributor.author
Weng, Honglei
dc.contributor.author
Holzhütter, Herrmann-Georg
dc.contributor.author
Zanger, Ulrich M.
dc.contributor.author
Bode, Johannes
dc.contributor.author
Vollmar, Brigitte
dc.contributor.author
Thomas, Maria
dc.contributor.author
Dooley, Steven
dc.date.accessioned
2018-06-08T04:20:26Z
dc.date.available
2015-12-18T09:11:42.476Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/17085
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-21265
dc.description.abstract
Background Disrupted bile secretion leads to liver damage characterized by
inflammation, fibrosis, eventually cirrhosis, and hepatocellular cancer. As
obstructive cholestasis often progresses insidiously, markers for the
diagnosis and staging of the disease are urgently needed. To this end, we
compiled a comprehensive data set of serum markers, histological parameters
and transcript profiles at 8 time points of disease progression after bile
duct ligation (BDL) in mice, aiming at identifying a set of parameters that
could be used as robust biomarkers for transition of different disease
progression phases. Results Statistical analysis of the more than 6,000 data
points revealed distinct temporal phases of disease. Time course correlation
analysis of biochemical, histochemical and mRNA transcript parameters
(=factors) defined 6 clusters for different phases of disease progression. The
number of CTGF-positive cells provided the most reliable overall measure for
disease progression at histological level, bilirubin at biochemical level, and
metalloproteinase inhibitor 1 (Timp1) at transcript level. Prominent molecular
events exhibited by strong transcript peaks are found for the transcriptional
regulator Nr0b2 (Shp) and 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1)
at 6 h. Based on these clusters, we constructed a decision tree of factor
combinations potentially useful as markers for different time intervals of
disease progression. Best prediction for onset of disease is achieved by
fibronectin (Fn1), for early disease phase by Cytochrome P450 1A2 (Cyp1a2),
passage to perpetuation phase by collagen1α-1 (Col1a1), and transition to the
progression phase by interleukin 17-a (Il17a), with early and late progression
separated by Col1a1. Notably, these predictions remained stable even for
randomly chosen small sub-sets of factors selected from the clusters.
Conclusion Our detailed time-resolved explorative study of liver homogenates
following BDL revealed a well-coordinated response, resulting in disease phase
dependent parameter modulations at morphological, biochemical, metabolic and
gene expression levels. Interestingly, a small set of selected parameters can
be used as diagnostic markers to predict disease stages in mice with
cholestatic liver disease.
en
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Systems biology
dc.subject
Cell proliferation
dc.subject
Bile duct ligation
dc.subject
Morphological profiling
dc.subject
Virtual liver network
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
dc.title
Pathobiochemical signatures of cholestatic liver disease in bile duct ligated
mice
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
BMC Systems Biology. - 9 (2015), Artikel Nr. 83
dcterms.bibliographicCitation.doi
10.1186/s12918-015-0229-0
dcterms.bibliographicCitation.url
http://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-015-0229-0
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDOCS_document_000000023633
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000005788
dcterms.accessRights.openaire
open access