title: The FLS (fatty liver Shionogi) mouse reveals local expressions of lipocalin-2, CXCL1 and CXCL9 in the liver with non-alcoholic steatohepatitis.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which carries a significant risk of progression to cirrhosis and hepatocellular carcinoma. Since NASH is a progressive but reversible condition, it is desirable to distinguish NASH from simple steatosis, and to treat NASH patients at an early stage. To establish appropriate diagnosis and therapy, the pathological mechanisms of the disease should be elucidated; however, these have not been fully clarified for both NASH and simple steatosis. This study aims to reveal the differences between simple steatosis and NASH.
  
  
  METHODS
  This study used fatty liver Shionogi (FLS) mice as a NASH model, for comparison with dd Shionogi (DS) mice as a model of simple steatosis. Genome-wide gene expression analysis was performed using Affymetrix GeneChip Mouse Genome 430 2.0 Array, which contains 45101 probe sets for known and predicted genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to investigate gene expression changes and protein localizations.
  
  
  RESULTS
  DNA microarray analysis of the liver transcriptomes and qRT-PCR of both types of mice revealed that LCN2, CXCL1 and CXCL9 mRNAs were overexpressed in FLS mouse livers. Immunohistochemistry showed that CXCL1 protein was mainly localized to steatotic hepatocytes. CXCL9 protein-expressing hepatocytes and sinusoidal endothelium were localized in some areas of inflammatory cell infiltration. Most interestingly, hepatocytes expressing LCN2, a kind of adipokine, were localized around almost all inflammatory cell clusters. Furthermore, there was a positive correlation between the number of LCN2-positive hepatocytes in the specimen and the number of inflammatory foci.
  
  
  CONCLUSIONS
  Overexpression and distinct localization of LCN2, CXCL1 and CXCL9 in the liver of fatty liver Shionogi mice suggest significant roles of these proteins in the pathogenesis of NASH.
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba 260-8670, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Semba
authors.forename: Motoi
authors.initials: M
authors.lastname: Nishimura
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishige
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ohno
authors.forename: Ken
authors.initials: K
authors.lastname: Nonaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sogawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Setsu
authors.initials: S
authors.lastname: Sawai
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.forename: Fumio
authors.initials: F
authors.lastname: Imazeki
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D022781:Hepatocytes; D007150:Immunohistochemistry; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018709:Statistics, Nonparametric; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D054360:Chemokine CXCL1; D054370:Chemokine CXCL9; C475895:Cxcl1 protein, mouse; C485969:Cxcl9 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse