Acetaminophen responsive miR-19b modulates SIRT1/Nrf2 signaling pathway in drug-induced hepatotoxicity

Previous studies suggest that activation of SIRT1 protects liver from acetaminophen (APAP)-induced injury, however, the detailed mechanism of SIRT1 modulation in this process is still incompletely. Therefore, this study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 mRNA and protein were markedly upregulated in human LO2 cells and mouse liver upon APAP exposure. In vitro, the specific knockdown of SIRT1 expression ultimately aggravated APAP-evoked cellular antioxidant defense in LO2 cells. Moreover, lentivirus mediated knockdown of hepatic SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, especially reduction of Nrf2 and subsequent downregulation of several antioxidant genes. Intriguingly, 30 mg/kg SRT1720, the specific SIRT1 activator, which greatly enhanced Nrf2 expression and antioxidant defense, and then eventually reversed APAP-induced hepatic liver injury in mice. Furthermore, APAP responsive ...