A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.
A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.
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DOI：
10.1038/s41467-022-35158-9
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发表时间：
2022-12-06
影响因子：
16.6
通讯作者：
Eslam, Mohammed
中科院分区：
文献类型：
--
作者：
Alharthi, Jawaher;Bayoumi, Ali;Thabet, Khaled;Pan, Ziyan;Gloss, Brian S.;Latchoumanin, Olivier;Lundberg, Mischa;Twine, Natalie A.;McLeod, Duncan;Alenizi, Shafi;Adams, Leon A.;Weltman, Martin;Berg, Thomas;Liddle, Christopher;George, Jacob;Eslam, Mohammed
Toll样受体（TLR）耐受性的破坏导致组织损伤，TLR的过度活化和随后的炎症后果已被认为是更严重形式的疾病和各种疾病（包括COVID-19和代谢（功能障碍）相关的脂肪肝疾病（MAFLD））的不良结局的风险因素。在这里，我们提供的证据表明，膜结合O-酰基转移酶域7（MBOAT 7）是TLR信号的负调节。在MAFLD患者和COVID-19患者中观察到的巨噬细胞中的MBOAT 7缺陷改变了膜磷脂组成。我们证明，这与花生四烯酸向促炎性类花生酸的重新分配，诱导内质网应激，线粒体功能障碍，以及重塑可访问的炎症相关的染色质景观，最终导致巨噬细胞对TLR的炎症反应。MBOAT 7的激活逆转了这些效应。这些结果进一步受到MBOAT 7 rs 8736（T）MAFLD风险变体的调节。我们的研究结果表明，MBOAT 7可以潜在地作为与TLR信号级联失调相关的疾病的治疗靶点进行探索。Toll样受体（TLR）的过度激活被认为是COVID-19和代谢（功能障碍）相关脂肪肝（MAFLD）中更严重疾病形式的风险因素。在这里，作者报告说，MBOAT 7在MAFLD和COVID-19患者的巨噬细胞中减少，并作为TLR信号传导的负调节剂。
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. Hyperactivation of the toll-like receptors (TLRs) have been implicated as risk factors for more severe forms of disease in COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here the authors report that MBOAT7 is reduced in macrophages of patients with MAFLD and COVID-19, and acts as a negative regulator of TLR signalling.
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影响因子：
3.8
作者：
Choi AJ;Ryter SW
通讯作者：
Ryter SW
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
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O'Riordan MX
影响因子：
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作者：
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通讯作者：
Voelker, Dennis R.
影响因子：
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作者：
Fagone, Paolo;Jackowski, Suzanne
通讯作者：
Jackowski, Suzanne
影响因子：
11.1
作者：
Dongiovanni P;Stender S;Pietrelli A;Mancina RM;Cespiati A;Petta S;Pelusi S;Pingitore P;Badiali S;Maggioni M;Mannisto V;Grimaudo S;Pipitone RM;Pihlajamaki J;Craxi A;Taube M;Carlsson LMS;Fargion S;Romeo S;Kozlitina J;Valenti L
通讯作者：
Valenti L