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.

MATERIALS & 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.

CONCLUSION:

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: Rie Ibusuki, Hirofumi Uto, Shiho Arima, Seiichi Mawatari, Yoshiko Setoguchi, Yuji Iwashita, Shinichi Hashimoto, Takuro Maeda, Shiro Tanoue, Shuji Kanmura, Makoto Oketani, Akio Ido, Hirohito Tsubouchi
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 33 Issue 10 Pg. 1549-56 (Nov 2013) ISSN: 1478-3231 [Electronic] United States
• PMID: 23682724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• 2-(6-fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-azabicyclo(2.2.1)heptane
• Amino Acids
• Azabicyclo Compounds
• Azo Compounds
• alpha-Defensins
• human neutrophil peptide 1
• C.I. direct red 80
• 2,2'-Dipyridyl
• Alanine Transaminase
• oil red O

Topics

• 2,2'-Dipyridyl (analogs & derivatives)
• Alanine Transaminase (blood)
• Amino Acids (metabolism)
• Animals
• Azabicyclo Compounds
• Azo Compounds
• Cell Proliferation
• Choline Deficiency
• Diet
• Fatty Liver (metabolism)
• Hepatic Stellate Cells (physiology)
• Humans
• Liver Cirrhosis (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Non-alcoholic Fatty Liver Disease
• alpha-Defensins (metabolism)