S-allylmercaptocysteine improves nonalcoholic steatohepatitis by enhancing AHR/NRF2-mediated drug metabolising enzymes and reducing NF-κB/IκBα and NLRP3/6-mediated inflammation

Abstract

Purpose

To investigate the novel molecular mechanisms of the antioxidant and anti-inflammatory properties of S-allylmercaptocysteine (SAMC) based on a transcriptomic study in a nonalcoholic steatohepatitis (NASH) rat model

Methods

NASH was induced in Sprague–Dawley rats by feeding with a high fat diet (HFD) for 12 weeks. 200 mg/kg SAMC was fed by oral gavage for 4 weeks from 9 to 12 week.

Results

SAMC co-administration attenuated HFD-induced liver injury, including the increased serum ALT, hepatic oxidative stress and inflammation. Transcriptomic analysis revealed that SAMC dramatically induced the XRE- and ARE-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and Nqo1. The nuclear translocation of the upstream regulator of xenobiotics metabolism, AHR, and regulator of antioxidant responses, NRF2, were significantly increased by SAMC treatment. Furthermore, SAMC counteracted the effects of HFD on NF-κB/IκB and NLRP3/6 pathways with decreasing protein levels of ASC, cleaved caspase-1, IL-18, and IL-1β. These results were further verified in another mice NASH model induced by an MCD diet with SAMC co-administration.

Conclusion

We propose that SAMC triggers AHR/NRF2-mediated antioxidant responses which may further suppress the NLRP3/6 inflammasome pathway and NF-κB activation, contributing to the improvement of NASH.

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Data availability

Not applicable.

Abbreviations

ARNT:

Ah receptor nuclear translocator

AKRs:

Aldo-reductases

ARE:

Antioxidant response element

AHR:

Aryl-hydrocarbon receptor

DMEs:

Drug metabolising enzymes

FFA:

Free fatty acid

H&E:

Haematoxylin and eosin

HFD:

High fat diet

MDA:

Malondialdehyde

MCD:

Methionine-chlorine deficient

NAS:

NAFLD activity scoring

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NRF2:

Nuclear factor (erythroid-derived 2)-like 2

NLRP3:

NOD-like receptor protein 3

NLRP6:

NOD-like receptor protein 6

SAMC:

S-allylmercaptocysteine

ALT:

Serum alanine aminotransferase

XRE:

Xenobiotic response element

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Funding

This research was funded by Seed Fund for Basic Research of University Research Committee, grant number 20161159263.

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QY: investigation, data curation, and writing—original draft preparation. YYL, Z-YX, and ECL: investigation and data curation. JX and GLT: conceptualization, methodology, supervision, resources, and writing—reviewing.

Corresponding authors

Correspondence to Jia Xiao or George L. Tipoe.

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We do not have any professional relationships with companies or manufacturers who will benefit from the results of the present study. We declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

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The manuscript does not contain clinical studies or patient data. The entire animal experiment procedures were approved by the Committee of Animal Use for Research and Teaching at The University of Hong Kong (CULATR No. 4618-18), which is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

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Yu, Q., Lee, Y., Xia, Z. et al. S-allylmercaptocysteine improves nonalcoholic steatohepatitis by enhancing AHR/NRF2-mediated drug metabolising enzymes and reducing NF-κB/IκBα and NLRP3/6-mediated inflammation. Eur J Nutr (2020). https://doi.org/10.1007/s00394-020-02305-1

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Keyword

  • S-allylmercaptocysteine
  • NASH
  • Inflammasome
  • Antioxidant responses
  • Xenobiotic responses