Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy

// Yongbiao Chen 1,2,* , Lizhi Lv 1,2,* , Huifeng Pi 3 , Weijia Qin 4 Jianwei Chen 5 , Dengfang Guo 6 , Jianyu Lin 1,2 , Xiaobing Chi 1,2 , Zhelong Jiang 1,2 , Hejun Yang 1,2 and Yi Jiang 1,2 1 Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China 2 Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China 3 Department of Occupational Health, Third Military Medical University, Chongqing, China 4 The 517th Hospital of PLA, Xinzhou, Shanxi, China 5 Department of Hepatobiliary Surgery, Fuzhou General Hospital of Fujian Medical University, Fuzhou, Fujian, China 6 Department of General Surgery, Mindong Hospital of Fujian Medical University, Fuan, Fujian, China * These authors have contributed equally to this work Correspondence to: Yi Jiang, email: // Keywords : dihydromyricetin; FOXO3a; autophagy; liver ischemia/reperfusion Received : August 08, 2016 Accepted : October 15, 2016 Published : October 25, 2016 Abstract Liver ischemia and reperfusion (I/R) injury is characterized by defective liver autophagy accompanied by alterations to the endogenous defense system. Dihydromyricetin (DHM) is a natural flavonoid that demonstrates a wide range of physiological functions, and has been implicated as a regulator of autophagy. This study investigates the protective effects of DHM pretreatment on liver injury caused by ischemia/reperfusion (I/R) and elucidates the potential mechanism of DHM-mediated protection. Mice were subjected to 60 minutes of ischemia followed by 5 hours of reperfusion. DHM (100 mg/kg bw/day) or the vehicle was administered daily by gavage 7 days before ischemia and immediately before reperfusion. In this study, DHM markedly decreased serum aminotransferase activity and inhibited liver I/R -stimulated apoptosis. Moreover, DHM exerted hepatoprotective effects by upregulating mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, and LC3. Autophagy inhibitor chloroquine or Atg5 knockdown blocked DHM -mediated elevation in liver function. Specifically, DHM significantly increased FOXO3a expression, and enhanced FOXO3a nuclear translocation and Ser588 phosphorylation modification. Importantly, the inhibition of FOXO3a with FOXO3a-siRNA in mice decreased DHM-induced autophagy-related genes and diminished the protective effects of DHM against liver I/R injury. In summary, these findings identify DHM as a novel hepatoprotective small molecule by elevating FOXO3a expression and nuclear translocation, stimulating autophagy-related genes and suppressing liver I/R-induced apoptosis, suggesting FOXO3a may have therapeutic value in liver cell protection in liver I/R injury.