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Published on: October 21, 2017
Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase
Irina G Kessova1, Ye-Shih Ho, Swan Thung
1Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
Because alcoholic liver disease has been linked to oxidative stress, we investigated the effect of a compromised antioxidant defense system, Cu, Zn-superoxide dismutase (Sod1) deficiency, on alcohol-induced liver injury. C57BL/129SV wild-type (Sod1(+/+)) and Sod1 knockout (Sod1(-/-)) mice were fed dextrose or ethanol (10% of total calories) liquid diets for 3 weeks. Histologic evaluation of liver specimens of Sod1(-/-) mice fed ethanol showed the development of liver injury ranging from mild to extensive centrilobular necrosis and inflammation. Sod1(+/+) mice fed ethanol showed mild steatosis; both Sod1(+/+) and Sod1(-/-) mice fed the dextrose diet had normal histology. Alanine transaminase levels were significantly elevated only in Sod1(-/-) mice fed ethanol. Cytochrome P450 2E1 (CYP2e1) activity was elevated about 2-fold by ethanol in Sod1(+/+) and Sod1(-/-) mice. Ethanol consumption increased levels of protein carbonyls and lipid peroxidation aldehydic products in the liver of Sod1(-/-) mice. Hepatic adenosine triphosphate (ATP) content was reduced dramatically in Sod1(-/-) mice fed ethanol in association with a decrease in the mitochondrial reduced glutathione (GSH) level and activity of MnSOD. Immunohistochemical determination of 3-nitrotyrosine (3NT) residues in liver sections of the Sod1 knockout mice treated with ethanol showed a significant increase of 3NT staining in the centrilobular areas. In conclusion, a rather moderate ethanol consumption promoted oxidative stress in Sod1(-/-) mice, with increased formation of peroxynitrite, protein carbonyls, and lipid peroxidation and decreased mitochondrial GSH and MnSOD. We speculate that the increased oxidative stress causes mitochondrial damage and reduction of ATP content, leading to alcoholic liver injury. This model may be useful in further mechanistic studies on alcohol-induced liver injury.
Insights
Mice lacking the antioxidant enzyme Cu, Zn-superoxide dismutase (Sod1) experienced significant liver injury and oxidative stress when fed ethanol. Sod1 deficiency exacerbates alcohol-induced liver damage, highlighting the role of antioxidant defenses.
Area of Science:
- Hepatology
- Biochemistry
- Toxicology
Background:
- Alcoholic liver disease (ALD) is associated with oxidative stress.
- The role of antioxidant defense systems in ALD pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the impact of compromised antioxidant defense, specifically Cu, Zn-superoxide dismutase (Sod1) deficiency, on alcohol-induced liver injury.
Main Methods:
- C57BL/129SV wild-type (Sod1(+/+)) and Sod1 knockout (Sod1(-/-)) mice were fed liquid diets containing either dextrose or ethanol (10% of total calories) for 3 weeks.
- Liver histology, alanine transaminase (ALT) levels, cytochrome P450 2E1 (CYP2e1) activity, oxidative stress markers (protein carbonyls, lipid peroxidation), adenosine triphosphate (ATP) content, mitochondrial reduced glutathione (GSH), MnSOD activity, and 3-nitrotyrosine (3NT) staining were assessed.
Main Results:
- Sod1(-/-) mice fed ethanol developed significant liver injury, including centrilobular necrosis and inflammation, unlike Sod1(+/+) mice which showed mild steatosis.
- Ethanol consumption increased CYP2e1 activity in both genotypes but elevated oxidative stress markers and reduced hepatic ATP, mitochondrial GSH, and MnSOD activity specifically in Sod1(-/-) mice.
- Increased 3-nitrotyrosine staining in centrilobular areas of Sod1(-/-) mice livers fed ethanol indicated peroxynitrite formation.
Conclusions:
- Compromised Sod1 antioxidant defense exacerbates alcohol-induced liver injury through increased oxidative stress, peroxynitrite formation, mitochondrial damage, and ATP depletion.
- This Sod1-deficient mouse model provides a valuable tool for studying the mechanisms of ALD.
