Possible Involvement of Nitric Oxide in Enhanced Liver Injury and Fibrogenesis during Cholestasis in Cytoglobin-deficient Mice.
This study clarified the role of Cygb, the fourth globin in mammals originally discovered in rat hepatic stellate cells (HSCs), in cholestatic liver disease. Bile duct ligation (BDL) augmented inflammatory reactions as revealed by increased infiltrating neutrophils, CD68+-macrophages, and chemokine expression in Cygb-/-mice. In these mice, impairment of bile canalicular indicated by the loss of CD10 expression, down-regulation of bile salt transporters, increased total bile acid, and massive apoptotic and necrotic hepatocytes occurred with the release of cytochrome c, activation of caspase 3, resulting in reduced animal survival compared to wild-type mice. In Cygb-/-mouse liver, all of NO metabolites and oxidative stress were increased. Treatment with NO inhibitor restrained all above phenotypes and restored CD10 expression in BDL Cygb-/-mice, while administration of NO donor aggravated liver damage in BDL-wild type mice to the same extent of BDL-Cygb-/-mice. N-acetylcysteine administration had a negligible effect in all groups. In mice of BDL for 1-3 weeks, expression of all fibrosis-related markers was significantly increased in Cygb-/-mice compared with wild-type mice. Thus, Cygb deficiency in HSCs enhances hepatocyte damage and inflammation in early phase and fibrosis development in late phase in mice subjected to BDL, presumably via altered NO metabolism.
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Tuong Thi
TT
Van Thuy
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Le Thi Thanh
LT
Thuy
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.|Synthetic Biology Laboratory, Graduate School of Medicine, Osaka City University, Osaka, Japan.|PhoenixBio Co. Ltd., Hiroshima, Japan.
Katsutoshi
K
Yoshizato
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Norifumi
N
Kawada
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002779:Cholestasis / Q000150:complications / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D000078842:Cytoglobin; D005914:Globins / Q000172:deficiency* / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015260:Neprilysin / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*
D002352:Carrier Proteins; C000627267:Cygb protein, mouse; C000627268:Cygb protein, rat; D000078842:Cytoglobin; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins; D009569:Nitric Oxide; D005914:Globins; D045304:Cytochromes c; D053148:Caspase 3; D015260:Neprilysin