title: Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Experimental Surgery, University Medicine Rostock, Schillingallee 69a, Rostock, 18057, Germany. kerstin.abshagen@uni-rostock.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.affiliation: Institute for Biochemistry, Computational Systems Biochemistry Group, Charité University Medicine Berlin, Berlin, 10117, Germany. matthias.koenig@charite.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: König
authors.affiliation: Institute for Biochemistry, Computational Systems Biochemistry Group, Charité University Medicine Berlin, Berlin, 10117, Germany. andreas.hoppe@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoppe
authors.affiliation: Institute for Experimental Surgery, University Medicine Rostock, Schillingallee 69a, Rostock, 18057, Germany. isabell-mueller86@web.de.
authors.forename: Isabell
authors.initials: I
authors.lastname: Müller
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany. matthias.ebert@umm.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebert
authors.affiliation: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany. honglei.weng@medma.uni-heidelberg.de.
authors.forename: Honglei
authors.initials: H
authors.lastname: Weng
authors.affiliation: Institute for Biochemistry, Computational Systems Biochemistry Group, Charité University Medicine Berlin, Berlin, 10117, Germany. hergo@charite.de.
authors.forename: Herrmann-Georg
authors.initials: HG
authors.lastname: Holzhütter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tuebingen, Tuebingen, Stuttgart, 70376, Germany. Uli.Zanger@ikp-stuttgart.de.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Department for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University of Düsseldorf, Düsseldorf, 40225, Germany. Johannes.Bode@med.uni-duesseldorf.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bode
authors.affiliation: Institute for Experimental Surgery, University Medicine Rostock, Schillingallee 69a, Rostock, 18057, Germany. brigitte.vollmar@med.uni-rostock.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tuebingen, Tuebingen, Stuttgart, 70376, Germany. Maria.Thomas@ikp-stuttgart.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany. Steven.Dooley@medma.uni-heidelberg.de.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002779:Cholestasis / Q000150:complications* / Q000209:etiology*; D018450:Disease Progression; D006801:Humans; D008026:Ligation / Q000009:adverse effects; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049490:Systems Biology; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers