S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury

• Published in: JCI insight Vol. 9; no. 2
• Main Authors: Cui, Qi, Jiang, Tingting, Xie, Xinya, Wang, Haodong, Qian, Lei, Cheng, Yanyan, Li, Qiang, Lu, Tingxu, Yao, Qinyu, Liu, Jia, Lai, Baochang, Chen, Chang, Xiao, Lei, Wang, Nanping
• Format: Journal Article
• Language: English
• Published: United States 23.01.2024
• Subjects: Acetaminophen - toxicity; Animals; Chemical and Drug Induced Liver Injury, Chronic - metabolism; Hepatocytes - metabolism; Humans; Mice; Pregnane X Receptor - metabolism; Molecular biology; Hepatology; Nitric oxide; Cell Biology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.172632

Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the S-nitrosylation of PXR (SNO-PXR) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for S-nitrosylation (SNO) modification. In hepatocytes, SNO suppressed both agonist-induced (rifampicin and SR12813) and constitutively active PXR (VP-PXR, a human PXR fused to the minimal transactivator domain of the herpes virus transcription factor VP16) activations. Furthermore, in acetaminophen-overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-/- mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of SNO-PXR. In conclusion, PXR is posttranslationally modified by SNO in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention.