Deletion of nardilysin prevents the development of steatohepatitis and liver fibrotic changes.
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.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shoko
S
Ishizu-Higashi
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hiroshi
H
Seno
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Eiichiro
E
Nishi
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshihide
Y
Matsumoto
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kozo
K
Ikuta
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Motoyuki
M
Tsuda
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshito
Y
Kimura
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yutaka
Y
Takada
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yuto
Y
Kimura
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yuki
Y
Nakanishi
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Keitaro
K
Kanda
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hideyuki
H
Komekado
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tsutomu
T
Chiba
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D002794:Choline / Q000032:analysis; D059305:Diet, High-Fat / Q000009:adverse effects; D060467:Disease Resistance / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000596:Amino Acids; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; C087976:nardilysin; D002794:Choline