A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes [Cut&Tag]
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ABSTRACT: The breakdown of toll-like receptor (TLR) tolerance results in tissue damage. Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a crucial negative regulator of TLR signaling. MBOAT7 deficiency in macrophages as observed in patients with metabolic (dysfunction) associated fatty liver disease (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 be exploited as a therapeutic target for diseases associated with dysregulation of the TLR signaling cascade.
ORGANISM(S): Homo sapiens
PROVIDER: GSE204964 | GEO | 2022/10/21
REPOSITORIES: GEO
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