Yan-Min Liu1, Jun Lv1, Qing-Lei Zeng1, Shen Shen1, Ji-Yuan Xing1, Ying-Ying Zhang1, Zhi-Hao Zhang1, Zu-Jiang Yu2. 1. Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China. 2. Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, Henan, China. Electronic address: Zu_JiangYu@163.com.
Abstract
BACKGROUND AND AIM: Acute liver failure (ALF) is an uncommon but serious disease still carrying a high mortality. This study aimed to investigate the mechanism of AMPK on D-GalN/LPS-induced ALF. METHODS: In this study, we utilized intraperitoneal injection of D-GalN/LPS to induce ALF model, and analyzed the expression of AMPK, inflammatory cytokines (TNF-α, IL-1β and IL-6), Foxo3A and autophagy-related genes (Atg-5, Beclin-1, Atg-7) by real-time quantitative polymerase chain reaction (RT-PCR) in liver tissue. We also examined the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of ALF mice. AMPK activation and inhibition of autophagy were induced by AICAR and 3-MA, respectively. Silence and overexpression of Foxo3A were performed by si-Foxo3A and pcDNA-Foxo3A, respectively. Lastly, the BMDM-conditioned medium (BMDM-CM) derived from BMDMs treated with AICAR and LPS were used to explore the effect of AMPK and Foxo3A on hepatocytes. RESULT: The expression of AMPK was decreased in liver tissue and the level of ALT and AST were increased in serum of D-GalN/LPS-induced ALF mice. AMPK activation ameliorated ALF by inhibiting inflammation (downregulated TNF-α, IL-1β and IL-6 expression), activating autophagy (increased Atg-5, Beclin-1 and Atg-7 expression) and upregulating Foxo3A expression. Silence of Foxo3A decreased AMPK-activated autophagy, but overexpressing Foxo3A attenuated liver failure by activating autophagy. In addition, AMPK activation alleviated liver failure in vitro. CONCLUSION: Thus, AMPK/Foxo3A/autophagy pathway may be an effective treatment approach to ameliorate ALF.
BACKGROUND AND AIM: Acute liver failure (ALF) is an uncommon but serious disease still carrying a high mortality. This study aimed to investigate the mechanism of AMPK on D-GalN/LPS-induced ALF. METHODS: In this study, we utilized intraperitoneal injection of D-GalN/LPS to induce ALF model, and analyzed the expression of AMPK, inflammatory cytokines (TNF-α, IL-1β and IL-6), Foxo3A and autophagy-related genes (Atg-5, Beclin-1, Atg-7) by real-time quantitative polymerase chain reaction (RT-PCR) in liver tissue. We also examined the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of ALFmice. AMPK activation and inhibition of autophagy were induced by AICAR and 3-MA, respectively. Silence and overexpression of Foxo3A were performed by si-Foxo3A and pcDNA-Foxo3A, respectively. Lastly, the BMDM-conditioned medium (BMDM-CM) derived from BMDMs treated with AICAR and LPS were used to explore the effect of AMPK and Foxo3A on hepatocytes. RESULT: The expression of AMPK was decreased in liver tissue and the level of ALT and AST were increased in serum of D-GalN/LPS-induced ALFmice. AMPK activation ameliorated ALF by inhibiting inflammation (downregulated TNF-α, IL-1β and IL-6 expression), activating autophagy (increased Atg-5, Beclin-1 and Atg-7 expression) and upregulating Foxo3A expression. Silence of Foxo3A decreased AMPK-activated autophagy, but overexpressing Foxo3Aattenuated liver failure by activating autophagy. In addition, AMPK activation alleviated liver failure in vitro. CONCLUSION: Thus, AMPK/Foxo3A/autophagy pathway may be an effective treatment approach to ameliorate ALF.