title: Iron increases liver injury through oxidative/nitrative stress in diabetic rats: Involvement of nitrotyrosination of glucokinase.
abstract: Excessive tissue iron levels are associated with the increase of oxidative/nitrative stress which contributes to tissue damage that may elevate the risk of diabetes. Therefore, we investigated the effects of iron on diabetes-associated liver injury and whether iron-related tyrosine nitration participated in this process. Rats were randomly divided into four groups: control, iron overload (300 mg/kg iron dextran, i.p.), diabetic (35 mg/kg of streptozotocin i.p. after administration of a high-fat diet) and diabetic simultaneously treated with iron. Iron supplement markedly increased diabetes-mediated liver damage and hepatic dysfunction by increasing liver/body weight ratio, serum levels of aspartate and alanine aminotransferase, and histological examination, which were correlated with elevated levels of lipid peroxidation, protein carbonyls and tyrosine nitration, oxidative metabolism of nitric oxide, and reduced antioxidant capacity. Consequently, the extent of oxidized/nitrated glucokinase was markedly increased in the iron-treated diabetic rats that contribute to a decrease in its expression and activity. Further studies revealed a significant contribution of iron-induced specific glucokinase nitration sites to its inactivation. In conclusion, iron facilitates diabetes-mediated elevation of oxidative/nitrative stress, simultaneously impairs liver GK, and can be a link between enzymatic changes and hepatic dysfunction. These findings may provide new insight on the role of iron in the pathogenesis of diabetes mellitus.
authors.affiliation: School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan 430074, PR China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Li
authors.forename: Hailing
authors.initials: H
authors.lastname: Li
authors.forename: Naihao
authors.initials: N
authors.lastname: Lu
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Feng
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D005941:Glucokinase / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009929:Organ Size; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D053719:Tandem Mass Spectrometry; D014443:Tyrosine / Q000378:metabolism
chemical_list: D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D014443:Tyrosine; D013311:Streptozocin; D007501:Iron; D005941:Glucokinase