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

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, Thomas Berg, Christopher Liddle, Jacob George and Mohammed Eslam ()
Additional contact information
Jawaher Alharthi: Westmead Hospital and University of Sydney
Ali Bayoumi: Westmead Hospital and University of Sydney
Khaled Thabet: Westmead Hospital and University of Sydney
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35158-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35158-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35158-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().