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; Mohammed Eslam

doi:10.1038/s41467-022-35158-9

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

Nat Commun. 2022 Dec 6;13(1):7430. doi: 10.1038/s41467-022-35158-9.

Authors

Jawaher Alharthi^{1

2}, Ali Bayoumi¹, Khaled Thabet^{1

3}, Ziyan Pan¹, Brian S Gloss⁴, Olivier Latchoumanin¹, Mischa Lundberg^{5

6

7}, Natalie A Twine⁵, Duncan McLeod⁸, Shafi Alenizi¹, Leon A Adams⁹, Martin Weltman¹⁰, Thomas Berg¹¹, Christopher Liddle¹, Jacob George¹, Mohammed Eslam¹²

Affiliations

¹ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.
² Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia.
³ Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 6111, Egypt.
⁴ Westmead Research Hub, Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁵ Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, NSW, Australia.
⁶ The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
⁷ The University of Queensland Faculty of Medicine, Brisbane, QLD, Australia.
⁸ Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, NSW, Australia.
⁹ Medical School, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia.
¹⁰ Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia.
¹¹ Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
¹² Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
COVID-19*
Humans
Liver Diseases*
Membrane Proteins
Toll-Like Receptors

Substances

Toll-Like Receptors
MBOAT7 protein, human
Acyltransferases
Membrane Proteins