TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in stroke through FTO/IGF2BP2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA893187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22019675_1.fastq.gz | Fastqsanger.gz | |||
| SRR22019675_2.fastq.gz | Fastqsanger.gz | |||
| SRR22019676_1.fastq.gz | Fastqsanger.gz | |||
| SRR22019676_2.fastq.gz | Fastqsanger.gz | |||
| SRR22019677_1.fastq.gz | Fastqsanger.gz |
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Project description:Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Mice were treated with TMAO in normal saline by oral gavage for 14 consecutive days. Then, mice were made into MCAO models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in stroke, microglia of MCAO mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Our results demonstrated that TMAO promoted the release of inflammatory cytokines in the brain of MCAO mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3, TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in stroke through FTO/IGF2BP2.
2023-09-06 | GSE216349 | GEO
Project description:To investigate the impact of TMAO on Myeloid cells. An RNA-seq analysis of myeloid cells was performed with and without TMAO treatment.
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Project description:TMAO promoted TREM-1 expression through NLRP3 inflammasome
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Project description:Circulating trimethylamine N-oxide (TMAO) participates in the pathogenesis of cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) originally regarded as the primary source of TMAO production. Here, we demonstrate that white adipose tissue (WAT) expressed FMO3 and its derived metabolic product TMAO causatively contribute to the systemic elevation of TMAO levels, WAT dysfunction, and metabolic diseases in ageing. We showed that FMO3 expression and TMAO levels are upregulated in WAT of naturally ageing animals and human subjects, as well as in a DNA damage-induced senescent adipocyte model, but not in the liver. This upregulation is due to p53 activation in mice and could be mitigated by calorie restriction in humans. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism, energy homeostasis, and lipid regulation in aged and high-fat diet-induced obese mice. Transcriptomic and histological analysis link these metabolic improvements to reduced senescence, fibrosis, and inflammation in WAT as well as a decrease in adipose-resident macrophages. LiP-small molecule mapping (LiP-SMap) analysis identified numerous novel TMAO-interacting proteins implicated in inflammasome activation within white adipocytes and macrophages. Mechanistically, TMAO facilitates inflammasome activation by binding to the inflammasome adaptor protein apoptosis-associated speck-like protein containing A CARD (ASC), thereby inducing its expression, caspase-1 activation, and subsequent interleukin-1β (IL-1β) production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
2025-08-23 | PXD066391 | Pride
Project description:Circulating trimethylamine N-oxide (TMAO) participates in the pathogenesis of cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) originally regarded as the primary source of TMAO production. Here, we demonstrate that white adipose tissue (WAT) expressed FMO3 and its derived metabolic product TMAO causatively contribute to the systemic elevation of TMAO levels, WAT dysfunction, and metabolic diseases in ageing. We showed that FMO3 expression and TMAO levels are upregulated in WAT of naturally ageing animals and human subjects, as well as in a DNA damage-induced senescent adipocyte model, but not in the liver. This upregulation is due to p53 activation in mice and could be mitigated by calorie restriction in humans. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism, energy homeostasis, and lipid regulation in aged and high-fat diet-induced obese mice. Transcriptomic and histological analysis link these metabolic improvements to reduced senescence, fibrosis, and inflammation in WAT as well as a decrease in adipose-resident macrophages. LiP-small molecule mapping (LiP-SMap) analysis identified numerous novel TMAO-interacting proteins implicated in inflammasome activation within white adipocytes and macrophages. Mechanistically, TMAO facilitates inflammasome activation by binding to the inflammasome adaptor protein apoptosis-associated speck-like protein containing A CARD (ASC), thereby inducing its expression, caspase-1 activation, and subsequent interleukin-1β (IL-1β) production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
2025-07-17 | GSE294785 | GEO
Project description:TMAO is gut microbiota dependent metabolite catalyzed by monooxygenase FMO3 from TMA. TMAO is positively assocaited with different metabolic diseases such as diabetes, chronic kidney disease, and atherosclerosis. We used microarray to analyze the genes regulated by TMAO treatment in primary rat hepatocytes to further understand the mechanistic view of TMAO action.
2019-08-22 | GSE135856 | GEO
Project description:Single nucleotide polymorphisms in intron 1 of the fat mass and obesity-associated (FTO) gene were found to be associated with an increased risk of adult obesity. Enhanced FTO expression in mice leads to hyperphagia, increased fat mass, and higher body weight. Neuronal-specific FTOâ??deleted mice have an identical lean body weight phenotype to global FTO-deleted mice. The physiological role of adipose FTO in the homeostasis of energy regulation remains to be elucidated. We used microarrays to elucidate the metabolic pathways that are regulated by FTO in the white fat. FTO flox/flox and Adiponectin-cre FTO flox/flox (AFO) mice were fed with chow diet. White fat tissues from epididymal adipose pad were harvested under ad lib condition for RNA isolation. Three independent pools of FTO flox/flox and AFO mouse white fat RNA were included in the study.
2016-07-03 | E-GEOD-65098 | biostudies-arrayexpress
Project description:HITS-CLIP is performed for the RNA-binding protein, IMP2/IGF2BP2, from E13.5 mouse brain.
2016-06-06 | E-MTAB-3636 | biostudies-arrayexpress
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228607 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228606 | GEO