Loss of RXRα, the shared heterodimerization partner of CAR and PXR, protected mice from APAP toxicity primarily by regulating the expression of Gst enzymes.34 Our current results showed that unlike CAR and PXR, activation

of LXR was beneficial in relieving APAP hepatotoxicity. The hepatoprotective effect of LXR may have resulted from the combined suppression of protoxic P450s and induction of antitoxic phase II enzymes Gst and Sult. RG-7204 Suppression of Cyp3a11 by LXR was opposite to the induction of the same enzyme in CAR/PXR-activated mice.32, 33 Induction of Cyp1a2, observed in CAR/PXR-activated mice,32, 33 was absent in LXR Tg mice. Suppression of Cyp3a by LXR was previously reported,22 which was proposed to be the result of the cross-suppression of CAR by LXR.36 We now provide evidence suggesting that LXR may also suppress Cyp3a11 by antagonizing the positive regulation of Cyp3a11 by PXR. The suppression of Cyp2e1 by LXR has not been reported. Cyp2e1 is better known for its post-transcriptional

regulation. LXR has recently been shown to regulate the E3 ubiquitin ligase-inducible Birinapant molecular weight degrader of the LDLR (Idol).37 It remains to be determined whether LXR can regulate the expression or activity of Cyp2e1 through a post-transcriptional mechanism. Among the LXR responsive phase II enzymes, the activation of Sult2a1 gene expression and lack of Ugt1a1 regulation by LXR have been reported.22 The isoform-specific regulation of Gst was intriguing. We reasoned the combined induction of Gstα and Gstμ classes and suppression of Gstπ may have contributed to the hepatoprotective role of LXR. The suppression of Gstπ in LXR-activated mice was consistent with the previous report that mice that lacked Gstπ were

resistant to APAP hepatotoxicity.17 In contrast, an induction Farnesyltransferase of Gstπ in CAR-activated mice was associated with the sensitizing effect.32 Our promoter analysis suggested that Gstμ1 and Gstπ1 gene promoters were positively and negatively regulated by LXR, respectively. The induction of Gstα and Gstμ isoforms was reminiscent of the effect of FXR, whose activation has recently been linked to protection against APAP-induced hepatic toxicity.35 In summary, the current study demonstrated that LXR may represent a potential therapeutic target for the prevention and treatment of APAP overdoses via induction of APAP-detoxifying/clearance enzymes and suppression of protoxic P450 enzymes. The authors thank Dr. David Mangelsdorf for LXR DKO mice and Dr. Song Li for synthesizing TO1317. Additional Supporting Information may be found in the online version of this article. “
“AASLD, the American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; RCT, randomized, controlled trial; RFA, radiofrequency ablation; US, ultrasound.