Unknown

Dataset Information

0

Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency.


ABSTRACT: Alpha-1-antitrypsin deficiency is a genetic disorder resulting in the expression of misfolded mutant protein that can polymerize and accumulate in hepatocytes, leading to liver disease in some individuals. Transgenic PiZ mice are a well-characterized model, which express human alpha-1-antitrypsin mutant Z protein (ATZ protein) and faithfully recapitulate the human liver disease. Liver tissue expressing alpha-1-antitrypsin mutant Z protein exhibits inflammation, injury and replacement of damaged cells. Fibrosis and hepatocellular carcinoma (HCC) develop in aging PiZ mice. In this study, microarray analysis was performed comparing young PiZ (ZY) mice to wild-type (WY), and indicated that there were alterations in gene expression levels that could influence a number of pathways leading to liver disease. Redox-regulating genes were up-regulated in ZY tissue, including carbonyl reductase 3 (CBR3), glutathione S-transferase alpha 1 + 2 (GSTA(1 + 2)) and glutathione S-transferase mu 3 (GSTM3). We hypothesized that oxidative stress could develop in Z mouse liver, contributing to tissue damage and disease progression with age. The results of biochemical analysis of PiZ mouse liver revealed that higher levels of reactive oxygen species (ROS) and a more oxidized, cellular redox state occurred in liver tissue from ZY mice than WY. ZY mice showed little evidence of oxidative cellular damage as assessed by protein carbonylation levels, malondialdehyde levels and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG) staining. Aging liver tissue from PiZ older mice (ZO) had elevated ROS, generally lower levels of antioxidant enzymes than younger mice and evidence of cellular damage. These data indicate that oxidative stress is a contributing factor in the development of liver disease in this model of alpha-1-antitrypsin deficiency.

SUBMITTER: Marcus NY 

PROVIDER: S-EPMC3510980 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC3871221 | BioStudies
2014-01-01 | S-EPMC4161314 | BioStudies
1000-01-01 | S-EPMC2633144 | BioStudies
2010-01-01 | S-EPMC2928671 | BioStudies
2019-01-01 | S-EPMC6953066 | BioStudies
2012-11-08 | E-GEOD-36478 | ArrayExpress
2020-01-01 | S-EPMC7406265 | BioStudies
2018-01-01 | S-EPMC5925576 | BioStudies
2017-01-01 | S-EPMC5675605 | BioStudies
2020-01-01 | S-EPMC7567128 | BioStudies