AIBP-mediated Cholesterol Efflux Instructs Hematopoietic Stem and Progenitor Cell Fate
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA503977 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8163631.fastq.gz | Fastqsanger.gz | |||
| SRR8163632.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are underexplored. Here we report that a novel somite-derived pro-hematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch upregulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide ChIP-seq, RNA-seq, and ATAC-seq indicate that Srebp2 trans-regulates Notch pathway genes required for hematopoiesis. Our studies outline a novel AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
2019-05-23 | GSE122204 | GEO
Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
| S-EPMC6469354 | biostudies-literature
Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
2025-06-11 | PXD064538 | Pride
Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
2025-06-11 | PXD064532 | Pride
Project description:Impaired cholesterol efflux pathways is a hallmark of lung adenocarcinoma. We used single cell RNA sequencing (scRNA-seq) to analyze the impact of defective cholesterol efflux on cell diversity in lung tumor
2023-06-01 | GSE226597 | GEO
Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.
2018-11-17 | GSE109998 | GEO
Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.
2018-11-17 | GSE109997 | GEO
Project description:Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNg-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.
2019-11-28 | GSE126378 | GEO
Project description:ATP binding cassette subfamily member 1 (ABCA1) and G1 (ABCG1) are cholesterol efflux transporter to prevent excess intracellular cholesterol accumulation. We here report the deletion of Abca1 and Abcg1 results in the significant increased expression of Cd38, a multi-faceted ectoenzyme with NADase activity.
2024-04-17 | GSE234507 | GEO
Project description:The relation of serial changes in plaque morphology of obstructive nonculprit lesions to HDL efflux, inflammation and transcriptome perturbations in response to high-dose statin therapy (YELLOW II study). YELLOW II is a prospective single center study. Stable patients who were scheduled for elective coronary angiography and/or coronary artery stenting were screened for this study. The final target population were patients with multivessel disease requiring staged intervention, culprit vessel initially and non-culprit vessel later, with maxLCBI4mm greater than 150 by NIRS. Patients underwent PCI for a culprit lesion followed by OCT and NIRS/IVUS of an obstructive non-culprit lesion (NCL). All subjects received rosuvastatin, 40 mg every day for 8-12 weeks. The NCL was reimaged and underwent intervention as a part of staged intervention. Blood samples were obtained for cholesterol efflux capacity (CEC) quantification and peripheral PBMC isolation. Despite the extensive evidence for the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects in remain elusive. In a prospective study, 85 patients with stable multivessel coronary artery disease underwent percutaneous coronary intervention for a culprit lesion followed by intracoronary multi-modality imaging including optical coherence tomography (OCT) of an obstructive NCL. All subjects received 40 mg of rosuvastatin every day for 8-12 weeks, when the NCL was reimaged and intervention was performed. Blood samples were drawn at both times to assess cholesterol efflux capacity (CEC) and transcriptomic profile in peripheral blood mononuclear cells (PBMC).
2016-10-29 | GSE86216 | GEO