Article first published online: 30 NOV 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 6, pages 2208–2217, December 2011
How to Cite
Saini, S. P.S., Zhang, B., Niu, Y., Jiang, M., Gao, J., Zhai, Y., Hoon Lee, J., Uppal, H., Tian, H., Tortorici, M. A., Poloyac, S. M., Qin, W., Venkataramanan, R. and Xie, W. (2011), Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in mice. Hepatology, 54: 2208–2217. doi: 10.1002/hep.24646
Potential conflict of interest: Nothing to report.
This work was supported, in part, by National Institutes of Health grant nos. DK083952 and ES019629 (to W.X.) and NSFC grant no. 31071027 (to Y.Z.).
- Issue published online: 30 NOV 2011
- Article first published online: 30 NOV 2011
- Accepted manuscript online: 2 SEP 2011 09:29AM EST
- Manuscript Accepted: 4 AUG 2011
- Manuscript Received: 11 MAY 2011
Overdose of acetaminophen (APAP), the active ingredient of Tylenol, is the leading cause of drug-induced acute liver failure in the United States. As such, it is necessary to develop novel strategies to prevent or manage APAP toxicity. In this report, we reveal a novel function of the liver X receptor (LXR) in preventing APAP-induced hepatotoxicity. Activation of LXR in transgenic (Tg) mice or by an LXR agonist conferred resistance to the hepatotoxicity of APAP, whereas the effect of LXR agonist on APAP toxicity was abolished in LXR-deficient mice. The increased APAP resistance in LXR Tg mice was associated with increased APAP clearance, increased APAP sulfation, and decreased formation of toxic APAP metabolites. The hepatoprotective effect of LXR may have resulted from the induction of antitoxic phase II conjugating enzymes, such as Gst and Sult2a1, as well as the suppression of protoxic phase I P450 enzymes, such as Cyp3a11 and Cyp2e1. Promoter analysis suggested the mouse Gst isoforms as novel transcriptional targets of LXR. The suppression of Cyp3a11 may be accounted for by the inhibitory effect of LXR on the PXR-responsive transactivation of Cyp3a11. The protective effect of LXR in preventing APAP toxicity is opposite to the sensitizing effect of pregnane X receptor, constitutive androstane receptor, and retinoid X receptor alpha. Conclusion: We conclude that LXR represents a potential therapeutic target for the prevention and treatment of Tylenol toxicity. (HEPATOLOGY 2011)