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A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes

Author

Listed:
  • Jawaher Alharthi

    (Westmead Hospital and University of Sydney
    Taif University)

  • Ali Bayoumi

    (Westmead Hospital and University of Sydney)

  • Khaled Thabet

    (Westmead Hospital and University of Sydney
    Minia University)

  • Ziyan Pan

    (Westmead Hospital and University of Sydney)

  • Brian S. Gloss

    (Westmead Institute for Medical Research)

  • Olivier Latchoumanin

    (Westmead Hospital and University of Sydney)

  • Mischa Lundberg

    (Commonwealth Scientific and Industrial Research Organisation
    The University of Queensland
    The University of Queensland Faculty of Medicine)

  • Natalie A. Twine

    (Commonwealth Scientific and Industrial Research Organisation)

  • Duncan McLeod

    (Westmead Hospital)

  • Shafi Alenizi

    (Westmead Hospital and University of Sydney)

  • Leon A. Adams

    (University of Western Australia)

  • Martin Weltman

    (Nepean Hospital)

  • Thomas Berg

    (Leipzig University Medical Center)

  • Christopher Liddle

    (Westmead Hospital and University of Sydney)

  • Jacob George

    (Westmead Hospital and University of Sydney)

  • Mohammed Eslam

    (Westmead Hospital and University of Sydney)

Abstract

The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.

Suggested Citation

  • Jawaher Alharthi & Ali Bayoumi & Khaled Thabet & Ziyan Pan & Brian S. Gloss & Olivier Latchoumanin & Mischa Lundberg & Natalie A. Twine & Duncan McLeod & Shafi Alenizi & Leon A. Adams & Martin Weltman, 2022. "A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35158-9
    DOI: 10.1038/s41467-022-35158-9
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    References listed on IDEAS

    as
    1. A. Phillip West & Igor E. Brodsky & Christoph Rahner & Dong Kyun Woo & Hediye Erdjument-Bromage & Paul Tempst & Matthew C. Walsh & Yongwon Choi & Gerald S. Shadel & Sankar Ghosh, 2011. "TLR signalling augments macrophage bactericidal activity through mitochondrial ROS," Nature, Nature, vol. 472(7344), pages 476-480, April.
    2. Khaled Thabet & Anastasia Asimakopoulos & Maryam Shojaei & Manuel Romero-Gomez & Alessandra Mangia & William L. Irving & Thomas Berg & Gregory J. Dore & Henning Grønbæk & David Sheridan & Maria Lorena, 2016. "MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C," Nature Communications, Nature, vol. 7(1), pages 1-8, November.
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