Inhibition of γ-glutamyltransferase ameliorates ischaemia-reoxygenation tissue damage in rats with hepatic steatosis

Background and Purpose: Hepatic steatosis may be associated with an increased γ-glutamyltransferase (γ-GT) levels. Ischaemia-reoxygenation (IR) injury causes several deleterious effects. We evaluated the protective effects of a selective inhibitor of γ-GT in experimentally induced IR injury in rats with obesity and steatosis. Experimental Approach: Otsuka Long-Evans Tokushima Fatty (OLETF) rats with hepatic steatosis were used in the current study. The portal vein and hepatic artery of left lateral and median lobes were clamped to induce ischaemia. Before clamping, 1 ml of saline (IR group) or 1-ml saline containing 1 mg·kg⁻¹ body weight of GGsTop (γ-GT inhibitor; IR-GGsTop group) was injected into the liver via the inferior vena cava. Blood flow was restored after at 30 min of the start of ischaemia. Blood was collected before, at 30 min after ischaemia and at 2 h and 6 h after reoxygenation. All the animals were killed at 6 h and the livers were collected. Key Results: Treatment with GGsTop resulted in significant reduction of serum ALT, AST and γ-GT levels and hepatic γ-GT, malondialdehyde, 4-hydroxy-2-nonenal and HMGB1 at 6 h after reoxygenation. Inhibition of γ-GT retained normal hepatic glutathione levels. There was prominent hepatic necrosis in IR group, which is significantly reduced in IR-GGsTop group. Conclusion and Implications: Treatment with GGsTop significantly increased hepatic glutathione content, reduced hepatic MDA, 4-HNE and HMGB1 levels and, remarkably, ameliorated hepatic necrosis after ischaemia-reoxygenation. The results indicated that GGsTop could be an appropriate therapeutic agent to reduce IR-induced liver injury in obesity and steatosis.