REGγ deficiency ameliorates hepatic ischemia and reperfusion injury in a mitochondrial p66shc dependent manner in mice

Background: Hepatic ischemia and reperfusion (I/R) injury is a common problem faced by patients undergoing clinical liver transplantation and hepatectomy, but the specific mechanism of liver I/R injury has not been fully elucidated. The protein degradation complex 11S proteasome is involved in apoptosis, proliferation and cell cycle regulation by regulating the 11S proteasome regulatory complex (REG)gamma. The main objective of this study is to explore the role and specific mechanism of REG gamma in liver I/R. Methods: By constructing a model of in vivo hepatic I/R injury in mice and a model of hypoxia and reoxygenation (H/R) in isolated hepatocytes. First, the REG gamma expression were detected during hepatic I/R in mice. Second, to investigate the effects of REG gamma knockout (KO) on liver necrosis, inflammatory response, apoptosis and mitochondrial function. Finally, mouse liver Src homology collagen (p66shc) mitochondrial translocation was detected. Results: The expression of REG gamma was up-regulated during hepatic I/R. REG gamma KO had significantly reduced liver tissue infarct size, liver transaminases, inflammatory cells infiltration, inflammatory cytokine and activation of nuclear factor kappa-B (NF-kappa B) signaling pathway and cell apoptosis. REG gamma KO had significantly alleviated the mitochondrial damage, decreased the up-regulated level of cytochrome C, reactive oxygen species (ROS). REG gamma KO had significantly reduced p66shc mitochondrial translocation in mice. Conclusions: The experimental results of this study indicated that REG gamma has an important role in preventing liver I/R injury and may play a role through the mitochondrial p66shc signaling pathway.