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Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice

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 comp...

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Autores principales: Abshagen, Kerstin, König, Matthias, Hoppe, Andreas, Müller, Isabell, Ebert, Matthias, Weng, Honglei, Holzhütter, Herrmann-Georg, Zanger, Ulrich M., Bode, Johannes, Vollmar, Brigitte, Thomas, Maria, Dooley, Steven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654904/
https://www.ncbi.nlm.nih.gov/pubmed/26589287
http://dx.doi.org/10.1186/s12918-015-0229-0
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author Abshagen, Kerstin
König, Matthias
Hoppe, Andreas
Müller, Isabell
Ebert, Matthias
Weng, Honglei
Holzhütter, Herrmann-Georg
Zanger, Ulrich M.
Bode, Johannes
Vollmar, Brigitte
Thomas, Maria
Dooley, Steven
author_facet Abshagen, Kerstin
König, Matthias
Hoppe, Andreas
Müller, Isabell
Ebert, Matthias
Weng, Honglei
Holzhütter, Herrmann-Georg
Zanger, Ulrich M.
Bode, Johannes
Vollmar, Brigitte
Thomas, Maria
Dooley, Steven
author_sort Abshagen, Kerstin
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-015-0229-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-46549042015-11-22 Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice Abshagen, Kerstin König, Matthias Hoppe, Andreas Müller, Isabell Ebert, Matthias Weng, Honglei Holzhütter, Herrmann-Georg Zanger, Ulrich M. Bode, Johannes Vollmar, Brigitte Thomas, Maria Dooley, Steven BMC Syst Biol Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-015-0229-0) contains supplementary material, which is available to authorized users. BioMed Central 2015-11-20 /pmc/articles/PMC4654904/ /pubmed/26589287 http://dx.doi.org/10.1186/s12918-015-0229-0 Text en © Abshagen et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Abshagen, Kerstin
König, Matthias
Hoppe, Andreas
Müller, Isabell
Ebert, Matthias
Weng, Honglei
Holzhütter, Herrmann-Georg
Zanger, Ulrich M.
Bode, Johannes
Vollmar, Brigitte
Thomas, Maria
Dooley, Steven
Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title_full Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title_fullStr Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title_full_unstemmed Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title_short Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
title_sort pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654904/
https://www.ncbi.nlm.nih.gov/pubmed/26589287
http://dx.doi.org/10.1186/s12918-015-0229-0
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