Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity
32 Pages Posted: 3 Oct 2018More...
Previous studies suggest that activation of SIRT1 protects against acetaminophen (APAP)-induced liver injury, however, the underlying mechanism of SIRT1 modulation is still incompletely. This study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 expression were markedly upregulated in hepatocytes after APAP treatment. Knockdown SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, which was accompanied by the reduced expression of Nrf2 and subsequent downregulation of several antioxidant genes. Intriguingly, SRT1720, the specific SIRT1 activator, reversed APAP induced hepatic liver injury. Furthermore, the APAP-responsive decrease of miR-19b is an obligatory step for the induction of SIRT1. Moreover, hepatic miR-19b overexpression worsened the APAP-hepatotoxicity in mice livers. Together, our results supports the notion that the elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, at least in part by enhancing Nrf2-mediated antioxidant capacity in the liver.
Funding: This work was supported by National Natural Science Foundation of China (Grant No. 81100281 to W.H; Grant Nos 31772709 and 31572485 to D.W), Medical and Health Research Project from Yichang Science and Technology Bureau (No. A15301-35 to W. H), the new faculty startup research fund of China Three Gorges University (Grant No.KJ2014B023 to D.W).
Declaration of Interest: The authors declare no conflict of interest.
Ethical Approval: Animal experiment was approved by the Animal Care and Use Committee of China Three Gorges University (2016090A).
Keywords: SIRT1; APAP; Hepatotoxicity; Oxidative stress; miR-19b; Nrf2
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