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Comparative Study
. 2009 Jul;330(1):79-88.
doi: 10.1124/jpet.109.152983. Epub 2009 Apr 22.

Overexpression of peroxiredoxin 6 does not prevent ethanol-mediated oxidative stress and may play a role in hepatic lipid accumulation

James R Roede  1 , David J Orlicky, Aron B Fisher, Dennis R Petersen
Affiliations
Comparative Study

Overexpression of peroxiredoxin 6 does not prevent ethanol-mediated oxidative stress and may play a role in hepatic lipid accumulation

James R Roede et al. J Pharmacol Exp Ther. 2009 Jul.

Abstract (V体育ios版)

Oxidative stress is implicated in the etiology of many diseases, including alcoholic liver disease (ALD). Peroxiredoxin 6 is a cytosolic peroxidase that has been demonstrated to protect various tissues, such as skin, lung, and cardiac muscle, against acute oxidative insults. Consequently, peroxiredoxin 6 was hypothesized to also protect the liver from oxidative stress generated during the process of chronic ethanol ingestion. To test this, wild-type peroxiredoxin 6 knockout mice (KO), and transgenic peroxiredoxin 6 overexpressing mice (TG) were fed an ethanol-containing diet. Various biomarkers of ALD were assessed, along with the effects of chronic ethanol consumption on the antioxidant defenses. After 9 weeks of ethanol consumption, all backgrounds exhibited elevations of plasma alanine aminotransferase activity, hepatosteatosis, CYP2E1 induction, and lipid peroxidation; however, hepatic triglyceride accumulation seemed to be exacerbated in ethanol-fed TG mice. Differences in antioxidant protein expression and activity in response to chronic ethanol consumption were also observed. Examples include significant inductions of catalase and glutathione transferase activity in ethanol-fed KO and TG mice, along with elevated levels of glutathione peroxidase activity. These alterations in antioxidant defenses could be attributed to either compensatory responses due to the genetic manipulations or ethanol-mediated responses. In conclusion, both ethanol-fed KO and ethanol-fed TG mice developed early stage ALD and peroxiredoxin 6 may play a role in ethanol-mediated hepatic lipid accumulation. VSports手机版.

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Figures

Fig. 1.
Fig. 1.
Chronic ethanol feeding results in steatosis. All ethanol-fed animals developed steatosis primarily in the midzonal and centrilobular regions of the hepatic lobule. Hematoxylin- and eosin-stained tissue sections. CV, central vein; PV, portal vein.
Fig. 2.
Fig. 2.
Chronic ethanol feeding results in CYP2E1 induction observed in Western blot (A and B) and activity measurements (C). n = 8, mean ± S.E.M. **, p < 0.01 (versus WT control); ***, p < 0.001 (versus WT control); †, p < 0.05 (versus KO control); ‡, p < 0.01 (versus KO control); #, p < 0.01 (versus TG control).
Fig. 3.
Fig. 3.
Chronic ethanol feeding causes lipid peroxidation and alterations in total GSH. Increased lipid peroxidation was visualized by staining for 4HNE-modified proteins (A and B) and TBARS assessment (C). Total GSH (D) was also measured in all animals. CV, central vein; PV, portal vein. n = 8, mean ± S.E.M. *, p < 0.05 (versus WT control); **, p < 0.01 (versus WT control); ***, p < 0.001 (versus WT control); †, p < 0.05 (versus TG control); ‡, p < 0.01 (versus KO control).
Fig. 4.
Fig. 4.
Immunohistochemical analysis of Prx6 expression in wild-type, KO, and TG mice. Note the positive nuclear staining in both wild-type and TG mice. Also note the mosaic pattern of positive staining in the TG mice. CV, central vein; PV, portal vein. Magnification, 200×.
Fig. 5.
Fig. 5.
Expression of Prx3 is basally elevated in KO mice compared with wild type. n = 3, mean ± S.E.M. **, p < 0.01 (versus WT control); ***, p < 0.001 (versus WT control); †, p < 0.05 (versus KO ethanol).
Fig. 6.
Fig. 6.
Effect of chronic ethanol and genotype on the activity of copper/zinc SOD (A), manganese SOD (B), catalase (C), glutathione peroxidase (D), glutathione reductase (E), and glutathione transferase (F). n = 4 to 8, mean ± S.E.M. *, p < 0.05 (versus WT control); **, p < 0.01 (versus WT control); ***, p < 0.001 (versus WT control); $, p < 0.05 (versus KO control); †, p < 0.01 (versus KO control); ‡, p < 0.001 (versus KO control); #, p < 0.05 (versus TG control); %, p < 0.001 (versus TG control); a, p < 0.05 (versus KO ethanol); b, p < 0.001 (versus KO ethanol).
Fig. 7.
Fig. 7.
Effect of chronic ethanol on NF-κB activation (A) and Nrf2-regulated gene expression (B–D). n = 3, mean ± S.E.M. *, p < 0.05 (versus WT control); **, p < 0.01 (versus WT control); †, p < 0.05 (versus TG control).
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