Characterization of ferroptosis in diabetic liver

Abstract

Diabetes is considered as an important cause of wide spectrum of liver disorders with the significant implication of oxidative stress. Cell death assumes a central role in the etiology of most of the liver pathologies. We aim to describe here the ferroptotic phenotype in diabetic liver. For that purpose, male C57BL/6 mice were divided into three groups: diabetic (streptozotocin-treated, 40 mg/kg in 5 consecutive days), diabetic treated with ferrostatin-1 (Fer-1, 1 mg/kg, from day 1-21) and vehicle-treated (control) animals. Diabetes induced biochemical/morphological alterations in the liver, including increases in ALT and TGC levels as well as fibrosis, hepatocytes volume and number of binuclear cells. These were accompanied by following changes at the molecular level: i) increase in accumulation of prooxidative (such as iron, lipofuscin and 4-HNE) and proinflammatory (HMGB1) parameters and ii) decrease in antioxidative-related (Nrf2, xCT, GPX4, GCL, HO-1) parameters. All of these ferroptosis-related events in the liver of diabetic animals were diminished with Fer-1 treatment. Our study reveals ferroptotic phenotype as an important part of the diabetes-related pathological changes in the liver. Also, the results suggest that targeting of ferroptosis represents promising approach in the prevention and treatment of liver diseases accompanying diabetes.