title: Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet.
abstract: BACKGROUND
  Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L-amino acid-defined (CDAA) diet.
  
  
  METHODS
  We generated transgenic mice expressing HNP-1 under the control of a β-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed.
  
  
  RESULTS
  HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more α-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1.
  
  
  CONCLUSIONS
  Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil-derived HNP-1 may contribute to the progression of NASH.
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ibusuki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uto
authors.forename: Shiho
authors.initials: S
authors.lastname: Arima
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mawatari
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Setoguchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iwashita
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Takuro
authors.initials: T
authors.lastname: Maeda
authors.forename: Shiro
authors.initials: S
authors.lastname: Tanoue
authors.forename: Shuji
authors.initials: S
authors.lastname: Kanmura
authors.forename: Makoto
authors.initials: M
authors.lastname: Oketani
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives; D000410:Alanine Transaminase / Q000097:blood; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D053961:Azabicyclo Compounds; D001391:Azo Compounds; D049109:Cell Proliferation; D002796:Choline Deficiency; D004032:Diet; D005234:Fatty Liver / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: C570237:2-(6-fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-azabicyclo(2.2.1)heptane; D000596:Amino Acids; D053961:Azabicyclo Compounds; D001391:Azo Compounds; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C009798:C.I. direct red 80; D015082:2,2'-Dipyridyl; D000410:Alanine Transaminase; C011049:oil red O
keywords: choline-deficient L-amino acid-defined diet; hepatic fibrosis; human neutrophil peptide-1; nonalcoholic steatohepatitis; transgenic mice