Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in mice

Abstract

Overdose of acetaminophen (APAP), the active ingredient of Tylenol, is the leading cause of drug-induced acute liver failure in the US. As such, it is necessary to develop novel strategies to prevent or manage APAP toxicity. In this report, we revealed a novel function of the liver X receptor (LXR) in preventing APAP-induced hepatotoxicity. Activation of LXR in transgenic 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 transgenic 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 anti-toxic Phase II conjugating enzymes such as Gst and Sult2a1, as well as suppression of pro-toxic 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 by the inhibitory effect of LXR on PXR-responsive transactivation of Cyp3a11. The protective effect of LXR in preventing APAP toxicity is opposite to the sensitizing effect of pregnane X receptor (PXR), constitutive androstane receptor (CAR), and retinoid X receptor α (RXRα). We conclude that LXR represents a potential therapeutic target for the prevention and treatment of Tylenol toxicity.

Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis

“…In contrast to these nuclear receptors, activation of the peroxisome proliferator-activated receptor alpha (PPARα) reduces APAP-induced injury, though this may not involve changes in metabolism (95–96). Similarly, farnesoid X receptor (FXR) and liver X receptor (LXR) activation appear to protect by decreasing expression of phase I enzymes and/or increasing expression of protective and detoxifying enzymes (97–98). However, these data are limited at best.…”

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

“…LXRa and LXRb are important regulators of cholesterol, fatty acid, and glucose homeostasis (Jakobsson et al, 2012). Activation of Lxr in mice increases APAP clearance through induction of phase II enzymes and abolishes its hepatotoxicity (Saini et al, 2011). On activation, FXR and LXR translocate to the nucleus, form a heterodimer with 9-cis retinoic acid receptor (RXR), and bind to response elements on the promoter of target genes (Jonker et al, 2012).…”

Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

“…On the contrary, activation of FXR induces enzymes involved in glutathione (involved in detoxification of metabolite) synthesis and thus protects against APAP-induced hepatotoxicity (130). Similarly, LXR activation also protects against APAP toxicity by suppression of phase I enzymes, activation of phase II (conjugation reaction) enzymes, and induction of enzymes involved in glutathione synthesis (131). Other nuclear factors involved in drug metabolism and the defense against oxidative stress are the aryl hydrocarbon receptor (AhR) and nuclear factor-E2-related factor (Nrf2).…”

“…In fact, a PXR antagonist (FLB-12) attenuates APAP hepatotoxicity in mice (135). A PPARα agonist (clofibrate) and LXR agonist (TO1317) have also demonstrated protective properties against APAP-induced hepatotoxicity (131, 136). Taken together, this information indicates that NRs play a central role in drug interactions and in DILI.…”