Background and aim: Preoperative fasting 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 role of the PI3K/AKT pathway and autophagy in the protective effect of preoperative fasting against liver IRI.

Methods: Primary cultured mouse hepatocytes or hepatocyte cell line (Hepa-1) and livers with or without fasting were exposed to hydrogen peroxide or I/R, respectively. In some groups, mice were also pretreated with LY294002 (AKT-specific inhibitor) 3-methyladenine (3MA, autophagy inhibitor), alone or simultaneously. Cell apoptosis, expression of P-AKT, T-AKT, LC3A, LC3B, ATG3 and BECLIN1 were analyzed. The liver injury was measured by the levels of serum aminotransferase, apoptosis and histological examination.

Results: Two days fasting triggered a significant upregulation of AKT activatity and expression of autophagy in liver tissue by Western blots. Fasting significantly reduced apoptosis induced by hydrogen peroxide (LDH), and improved liver IRI. Fasting activated PI3K/AKT pathway in hepatocytes. Functionally, LY294002 could abolish the AKT activation and attenuate the protective effect of fasting on hepatocytes after hydrogen peroxide treatment or I/R. Furthermore, Fasting also induced liver autophagy in vitro and in vivo. Intersetingly, 3MA could significantly diminish the protective effect of fasting.

Conclusion: This study demonstrated for the first time that AKT activation and autophagy are critical in fasting against liver ischemia reperfusion injury.

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