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

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	7430
Number of pages	19
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35158-9
Publication status	Published - Dec 2022

Access to Document

10.1038/s41467-022-35158-9Licence: CC BY

Cite this

Alharthi, J., Bayoumi, A., Thabet, K., Pan, Z., Gloss, B. S., Latchoumanin, O., Lundberg, M., Twine, N. A., McLeod, D., Alenizi, S., Adams, L. A., Weltman, M., Berg, T., Liddle, C., George, J., & Eslam, M. (2022). A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes. Nature Communications, 13(1), [7430]. https://doi.org/10.1038/s41467-022-35158-9

@article{1c3d2ac928804267a889316d2be031d2,

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

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.",

author = "Jawaher Alharthi and Ali Bayoumi and Khaled Thabet and Ziyan Pan and Gloss, {Brian S.} and Olivier Latchoumanin and Mischa Lundberg and Twine, {Natalie A.} and Duncan McLeod and Shafi Alenizi and Adams, {Leon A.} and Martin Weltman and Thomas Berg and Christopher Liddle and Jacob George and Mohammed Eslam",

note = "Funding Information: We would like to thank all the patients and healthy volunteers for their participation in this study. Cell Imaging and Electron Microscopy were performed at the Westmead Scientific Platforms, which are supported by the Westmead Research Hub, the Cancer Institute New South Wales, the National Health and Medical Research Council and the Ian Potter Foundation. M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Programme and investigator grants (APP2008983 and APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-35158-9",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "1",

}

Alharthi, J, Bayoumi, A, Thabet, K, Pan, Z, Gloss, BS, Latchoumanin, O, Lundberg, M, Twine, NA, McLeod, D, Alenizi, S, Adams, LA, Weltman, M, Berg, T, Liddle, C, George, J & Eslam, M 2022, 'A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes', Nature Communications, vol. 13, no. 1, 7430. https://doi.org/10.1038/s41467-022-35158-9

TY - JOUR

T1 - A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes

AU - Alharthi, Jawaher

AU - Bayoumi, Ali

AU - Thabet, Khaled

AU - Pan, Ziyan

AU - Gloss, Brian S.

AU - Latchoumanin, Olivier

AU - Lundberg, Mischa

AU - Twine, Natalie A.

AU - McLeod, Duncan

AU - Alenizi, Shafi

AU - Adams, Leon A.

AU - Weltman, Martin

AU - Berg, Thomas

AU - Liddle, Christopher

AU - George, Jacob

AU - Eslam, Mohammed

N1 - Funding Information: We would like to thank all the patients and healthy volunteers for their participation in this study. Cell Imaging and Electron Microscopy were performed at the Westmead Scientific Platforms, which are supported by the Westmead Research Hub, the Cancer Institute New South Wales, the National Health and Medical Research Council and the Ian Potter Foundation. M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Programme and investigator grants (APP2008983 and APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85143423035&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-35158-9

DO - 10.1038/s41467-022-35158-9

M3 - Article

C2 - 36473860

AN - SCOPUS:85143423035

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 7430

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this