Starvation-Mediated Autophagy Attenuates Liver Ischemia Reperfusion Injury By SIRT1 in Mice.

Abstract

Background and aims: Preoperative starvation is known to attenuate liver ischemia reperfusion injury (IRI). However, the exact mechanism behind this protective effect is unknown. This study was designed to investigate the roles and mechanisms of the protective effect of preoperative starvation against liver IRI. Methods: Primary cultured mouse hepatocytes or hepatocyte cell line (Hepa-1) and livers with or without starvation were exposed to hydrogen peroxide (H2O2) or I/R, respectively. In some groups, mice/hepatocytes were also pretreated with sirtinol (SIRT1-specific inhibitor) or 3-methyladenine (3MA, autophagy inhibitor), respectively. Expression of P62, LC3B and SIRT1 were analyzed in ischemic liver or H2O2 treated hepatocytes. The liver injury was measured by the levels of serum aminotransferase, apoptosis and histological examination. Results: Two days starvation triggered a significant upregulation expression of P62, LC3B and SIRT1 in liver tissue by immune blots. Furthermore, starvation also induced SIRT1/autophagy pathway in vitro. Importantly, Starvation significantly reduced apoptosis induced by H2O2, and attenuated liver IRI. Functionally, 3MA sirtinol abolished the starvation-mediated autophagy pathway in vivo and vitro, and significantly diminish the protective effect of starvation on hepatocytes after H2O2 treatment or liver I/R. Intersetingly, sirtinol significantly inhibited expression of SIRT1 induced by starvation, then repressed autophagy and recreated liver IRI. Conclusion: This study demonstrated for the first time that starvation attenuated liver IRI by SIRT1-mediated autophagy.