title: Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains.
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.
  
  
  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.
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Vikash
authors.initials: V
authors.lastname: Pandey
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Meryem
authors.initials: M
authors.lastname: Ralser
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Starmann
authors.affiliation: BIOCRATES Life Sciences AG, Innsbruck, Austria; LKH Wagna, Department of Internal Medicine, Wagna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Osprian
authors.affiliation: Rheumatology and Clinical Immunology, Charité-University Medicine, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grimm
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Hache
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany; Dahlem Centre for Genome Research and Medical Systems Biology, Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany; Dahlem Centre for Genome Research and Medical Systems Biology, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wierling
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D040901:Proteomics; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D011725:Pyridines