1. Academic Validation
  2. S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury

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

  • JCI Insight. 2023 Nov 30:e172632. doi: 10.1172/jci.insight.172632.
Qi Cui 1 Tingting Jiang 1 Xinya Xie 2 Haodong Wang 3 Lei Qian 1 Yanyan Cheng 1 Qiang Li 4 Tingxu Lu 2 Qinyu Yao 2 Jia Liu 2 Baochang Lai 2 Chang Chen 5 Lei Xiao 6 Nanping Wang 3
Affiliations

Affiliations

  • 1 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
  • 2 School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 3 Health Science Center, East China Normal University, Shanghai, China.
  • 4 School of Public Health, Xi'an Jiaotong University, Xi'an, China.
  • 5 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 6 Xi'an Jiaotong University, Xi'an, China.
Abstract

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 PXR S-nitrosylation (SNO) 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 SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (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 PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention.

Keywords

Cell Biology; Hepatology; Molecular biology; Nitric oxide.

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