Mannan‐binding lectin attenuates acetaminophen‐induced hepatotoxicity by regulating CYP2E1 expression via ROS‐dependent JNK/SP1 pathway

Mannan‐binding lectin (MBL) acts as a soluble pattern recognition molecule in the innate immune system, which is primarily produced by the liver. MBL deficiency occurs with high frequency in the population and is reported to be associated with susceptibility to several liver diseases. In the present study, we investigated the pathophysiological role of MBL in acetaminophen (APAP)‐induced hepatotoxicity. After APAP treatment, MBL‐deficient (MBL−/−) mice had significantly higher mortality and aggravated hepatic necrosis as well as elevated serum lactate dehydrogenase and alanine aminotransferase levels compared to control mice. The enhanced hepatotoxicity in MBL−/− mice was associated with increased concentration of APAP toxic metabolisms. Furthermore, we demonstrated here that genetic ablation of MBL resulted in excessive reactive oxygen species (ROS) production and enhanced c‐Jun N‐terminal kinase (JNK) activation, leading to up‐regulated specificity protein 1 (SP1) nuclear expression, thus promoted CYP2E1 hepatic expression and consequently exacerbated APAP‐induced liver injury in mice. Importantly, we have validated that MBL protected against APAP toxicity in human HepaRG cells in vitro with the same mechanism. Our study revealed an unexpected function of MBL in drug metabolism, thus providing new insight into the drug‐induced liver injury in patients with MBL deficiency.

• Publication year

  2019

• Venue

  European Journal of Immunology

• Publication date

  2019-02-12

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1002/eji.201847830PMID 30706943
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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