Deletion of nardilysin prevents the development of steatohepatitis and liver fibrotic changes

PLoS One. 2014 May 21;9(5):e98017. doi: 10.1371/journal.pone.0098017. eCollection 2014.

Abstract

Nonalcoholic steatohepatitis (NASH) is an inflammatory form of nonalcoholic fatty liver disease that progresses to liver cirrhosis. It is still unknown how only limited patients with fatty liver develop NASH. Tumor necrosis factor (TNF)-α is one of the key molecules in initiating the vicious circle of inflammations. Nardilysin (N-arginine dibasic convertase; Nrd1), a zinc metalloendopeptidase of the M16 family, enhances ectodomain shedding of TNF-α, resulting in the activation of inflammatory responses. In this study, we aimed to examine the role of Nrd1 in the development of NASH. Nrd1+/+ and Nrd1-/- mice were fed a control choline-supplemented amino acid-defined (CSAA) diet or a choline-deficient amino acid-defined (CDAA) diet. Fatty deposits were accumulated in the livers of both Nrd1+/+ and Nrd1-/- mice by the administration of the CSAA or CDAA diets, although the amount of liver triglyceride in Nrd1-/- mice was lower than that in Nrd1+/+ mice. Serum alanine aminotransferase levels were increased in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. mRNA expression of inflammatory cytokines were decreased in Nrd1-/- mice than in Nrd1+/+ mice fed the CDAA diet. While TNF-α protein was detected in both Nrd1+/+ and Nrd1-/- mouse livers fed the CDAA diet, secretion of TNF-α in Nrd1-/- mice was significantly less than that in Nrd1+/+ mice, indicating the decreased TNF-α shedding in Nrd1-/- mouse liver. Notably, fibrotic changes of the liver, accompanied by the increase of fibrogenic markers, were observed in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. Similar to the CDAA diet, fibrotic changes were not observed in Nrd1-/- mice fed a high-fat diet. Thus, deletion of nardilysin prevents the development of diet-induced steatohepatitis and liver fibrogenesis. Nardilysin could be an attractive target for anti-inflammatory therapy against NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / analysis
  • Animals
  • Choline / analysis
  • Diet, High-Fat / adverse effects
  • Disease Resistance / genetics
  • Female
  • Gene Deletion*
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / prevention & control*
  • Male
  • Metalloendopeptidases / deficiency*
  • Metalloendopeptidases / genetics*
  • Mice
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / prevention & control*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amino Acids
  • Tumor Necrosis Factor-alpha
  • Metalloendopeptidases
  • nardilysin
  • Choline

Grant support

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI 21229009, 23300117, 23590937, 24229005, 24590914, 24590916, 24659363, 25112707, 25130706, 25461021, 25860533, and 26293173; Research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Health and Labour Sciences Research Grants for Research on Intractable Diseases, Hepatitis, and The innovative development and the practical application of new drugs for hepatitis B from the Ministry of Health, Labour and Welfare, Japan; the Funding Program for Next-Generation World-leading Researchers (LS075), Grants-in Aid from the Ministry of Education, Culture, Science, Sports and Technology of Japan; Kobayashi Foundation for Cancer Research; The Naito Foundation; and Princess Takamatsu Cancer Research Foundation (13-24514). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.