Abstract
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 incomplete. 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 miR-19b played an important role in regulating SIRT1 expression, whereas overexpression miR-19b largely abolished the induction of SIRT1 by APAP in vitro and in vivo. Specific SIRT1 3'-UTR mutation, which disrupted the interaction of miRNA-3'UTR, and successfully abrogated the modulation by miR-19b. Notably, hepatic miR-19b overexpression worsened the APAP-induced hepatotoxicity. In general, our results support the notion that the strong elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect liver against the drug-induced damage, at least in part by enhancing Nrf2-mediated antioxidant capacity in the liver.