Zinc treatment prevents type 1 diabetes-induced hepatic oxidative damage, endoplasmic reticulum stress, and cell death, and even prevents possible steatohepatitis in the OVE26 mouse model: Important role of metallothionein

• Published in: Toxicology letters 2015-03, Vol.233 (2), p.114-124
• Main Authors: Liang, Tingting, Zhang, Quan, Sun, Weixia, Xin, Ying, Zhang, Zhiguo, Tan, Yi, Zhou, Shanshan, Zhang, Chi, Cai, Lu, Lu, Xuemian, Cheng, Mingliang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cell death; Cell Death - drug effects; Chemical and Drug Induced Liver Injury - prevention & control; Chickens; Collagen - metabolism; Damage; Diabetes Mellitus, Type 1 - complications; Diabetic complications; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; ER stress; Fatty Liver - prevention & control; Hepatic dysfunction; Injuries; Liver; Liver Function Tests; Liver injury; Metallothionein; Metallothionein - metabolism; Mice; Mice, Transgenic; Oxidative Stress - drug effects; Rats; Serums; Zinc; Zinc - therapeutic use
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2015.01.010

[Display omitted] •Six-month old OVE26 mice exhibit the increase of serum alanine aminotransferase.•Six-month old OVE26 mice exhibit significant hepatic pathological changes.•Zinc-treatment significantly prevented diabetes-induced hepatic abnormalities.•Mechanistically zinc treatment increased hepatic metallothionein expression. Whether zinc is able to improve diabetes-induced liver injury remains unknown. Transgenic type 1 diabetic (OVE26) mice develop hyperglycemia at 3 weeks old; therefore therapeutic effect of zinc on diabetes-induced liver injury was investigated in OVE26 mice. Three-month old OVE26 and age-matched wild-type mice were treated by gavage with saline or zinc at 5mg/kg body-weight every other day for 3 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level with liver histopathological and biochemical changes. OVE26 mice at 6 months old showed significant increases in serum ALT level and hepatic oxidative damage, endoplasmic reticulum stress and associated cell death, mild inflammation, and fibrosis. However, all these hepatic morphological and functional changes were significantly prevented in 3-month zinc-treated OVE26 mice. Mechanistically, zinc treatment significantly increased hepatic metallothionein, a protein with known antioxidant activity, in both wild-type and OVE26 mice. These results suggest that there were significantly functional, structural and biochemical abnormalities in the liver of OVE26 diabetic mice at 6 months old; however, all these changes could be prevented with zinc treatment, which was associated with the upregulation of hepatic metallothionein expression.