Renalase Attenuates Mouse Fatty Liver Ischemia/Reperfusion Injury through Mitigating Oxidative Stress and Mitochondrial Damage via Activating SIRT1

Abstract

Liver ischemia/reperfusion (IR) injury is a severe complication of liver surgery. Moreover, nonalcoholic fatty liver disease (NAFLD) patients are particularly vulnerable to IR injury, with higher rates of postoperative morbidity and mortality after liver surgeries. Our previous study found that renalase (RNLS) was highly sensitive and responsive to oxidative stress, which may be a promising biomarker for the evaluation of the severity of liver IR injury. However, the role of RNLS in liver IR injury remains unclear. In the present study, we intensively explored the role and mechanism of RNLS in fatty liver IR injury in vivo and in vitro. C57BL/6 mice were divided into 2 groups feeding with high-fat diet (HFD) and control diet (CD), respectively. After 20 weeks’ feeding, they were suffered from portal triad blockage and reflow to induce liver IR injury. Additionally, oleic acid (OA) and tert-butyl hydroperoxide (t-BHP) were used in vitro to induce steatotic hepatocytes and to simulate ROS burst and mimic cellular oxidative stress following portal triad blockage and reflow, respectively. Our data showed that RNLS was downregulated in fatty livers, and RNLS administration effectively attenuated IR injury by reducing ROS production and improving mitochondrial function through activating SIRT1. Additionally, the downregulation of RNLS in the fatty liver was mediated by a decrease of signal transduction and activator of transcription 3 (STAT3) expression under HFD conditions. These findings make RNLS a promising therapeutic strategy for the attenuation of liver IR injury.

Remifentanil up‐regulates HIF1α expression to ameliorate hepatic ischaemia/reperfusion injury via the ZEB1/LIF axis

“…In this paper, we established an I/R‐induced hepatic injury model in C57BL/6 mice, following established procedures 28,29 and hypoxia‐induced cell line model in NCTC‐1469 cells. By using a knockdown strategy, histological approaches and molecular methods, we further demonstrated that remifentanil ameliorates I/R‐induced hepatic injury through the regulation of HIF1α and ZEB1/LIF axis.…”

Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

“…In addition, hepatic renalase expression increases in response to oxidative stress in the mouse liver with induced ischemia-reperfusion (IR) injury, suggesting that renalase protects tissues (16). Recently, the downregulation of renalase in nonalcoholic fatty liver disease (NAFLD) and its protective role against liver IR injury has been reported, indicating that the downregulation of renalase may be involved in the susceptibility of the fatty liver to IR injury (17). The progression of liver diseases such as NAFLD and NASH is considered to be suppressed by the inhibitory effects of renalase on inflammation, oxidative stress, and apoptosis.…”

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

“…Activation of the c-Jun Nterminal kinase-1 (JNK1) contributes to increased mitochondrial oxidative stress (as assessed by the GSSG:GSH ratio) and decreased ATP levels, which trigger mPTP opening and hepatocyte apoptosis [69]. Aberrant regulation of the Sirt1/STAT3 signaling pathway promotes mitochondrial damage and elevated production of ROS in NAFLD [70]. The noncanonical KEAP1-NFE2L2 pathway is a potential therapeutic target in NAFLD because it promotes antioxidative response against lipotoxicity in the hepatocytes and the mouse liver tissues [71].…”