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Obesity disrupts cellular cholesterol homeostasis to inhibit the homeostatic clonal expansion of ST2hi VAT Treg cells

ABSTRACT: Obesity disrupts cellular cholesterol homeostasis to inhibit the homeostatic clonal expansion of ST2hi VAT Treg cells

PROVIDER: PRJNA1018934 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26115510_1.fastq.gz	Fastqsanger.gz
	SRR26115510_2.fastq.gz	Fastqsanger.gz
	SRR26115511_1.fastq.gz	Fastqsanger.gz
	SRR26115511_2.fastq.gz	Fastqsanger.gz
	SRR26115512_1.fastq.gz	Fastqsanger.gz

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Obesity disrupts cellular cholesterol homeostasis to inhibit the homeostatic clonal expansion of ST2hi VAT Treg cells

Project description:Regulatory T (Treg) cells are highly enriched in the visceral adipose tissue (VAT) to maintain metabolic homeostasis, but they are lost during obesity. Currently, how VAT Treg cells rewire cellular metabolism to support their homeostatic clonal expansion, and whether this process is disrupted in obesity, is unclear. Here, we found that cholesterol metabolism was uniquely upregulated in VAT-, but not other non-lymphoid-tissue Treg cells. Disrupting cholesterol homeostasis (CH) by Treg-specific deletion of Srebf2 led to a specific loss of VAT Treg cells and enhanced obesity-induced systemic metabolic dysfunction. Mechanistically, Srebf2-mediated CH potentiated strong TCR signaling, which specifically promoted the clonal expansion of ST2hi, but not other, VAT Treg subsets. However, long-term high-fat-diet feeding disrupted VAT Treg CH and impaired ST2hi VAT Treg clonal expansion. Restoring Treg CH rescued VAT Treg accumulation in obese mice, suggesting CH modulation could be a potential option for Treg-targeted therapies in obesity-associated metabolic diseases.

2025-01-10 | GSE243563 | GEO

The impact of Srebf2 deletion on the transcriptional phenotype of visceral adipose tissue (VAT) regulatory T (Treg) cells

Project description:Regulatory T (Treg) cells are highly enriched in the visceral adipose tissue (VAT) to maintain metabolic homeostasis, but they are lost during obesity. VAT Treg cells exhibit enhanced Srebf2-dependent cholesterol metabolism compared lymphoid tissue Tregs at steady state, but this metabolic pathway is disrupted during obesity. Therefore, the goal of this study is to determine the impact of Treg-specific Srebf2 deletion on the transcriptional phenotype of bulk Foxp3+ VAT or splenic Tregs.

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The impact of IL-33 on Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs

Project description:Tregs are highly enriched in the eVAT of male mice. We show that ST2+ VAT Tregs preferentially upregulate and depend on Srebf2-mediated cholesterol metabolism compared their spleen Treg or ST2- VAT Treg counterparts. However, it is unclear whether this increased reliance on cholesterol metabolism is a consequence elevated IL-33 signaling in ST2+ Tregs. Therefore, the goal of experiment is to determine whether IL-33 signaling influences Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs in vivo.

2025-01-10 | GSE272435 | GEO

Cholesterol homeostatic regulator SREBP2 promotes macrophage alternative activation and allergic airway inflammation

Project description:Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.

2023-04-30 | GSE188356 | GEO

Cholesterol homeostatic regulator SREBP2 promotes macrophage alternative activation and allergic airway inflammation

Project description:Cholesterol homeostatic regulator SREBP2 promotes macrophage alternative activation and allergic airway inflammation

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Metabolic control in VAT by Tregs through OSM-mediated suppression of adipogenesis

Project description:Regulatory T cells (Tregs) play diverse roles in tissue homeostasis. In visceral adipose tissue (VAT), resident Tregs, enriched with PPARγ, are clonally expanded in a IL-33 dependent manner. However, the tissue-specific functions of VAT Tregs, with unique transcriptome compared to spleen or other peripheral tissues, remain largely unknown. We identified two PPARγ+ mesenchymal stromal cells in VAT (VmSCs), named VmSC4s (PPARγ+Thy1-) and 5s (PPARγ+Thy1+). Lineage-tracing and transcriptome analysis revealled that VmSC4s contain precursors for VmSC5s. We also demonstrated that VAT Tregs directly suppress adipogenic differentation of VmSC5s through Oncostain M (OSM) to promote insulin sensitivity and glucose tolerance. Thus, VAT-Treg-derived OSM and VmSCs-displayed OSMR maintain tissue homeostasis via limiting the differentiation of dysfunctional adipocytes, which provide therapeutic targets for treating obesity and diabetes.

2023-08-01 | GSE226889 | GEO

HIV-1 permanently disrupts homeostatic ILCs and expands inflammatory TCF7-dependent memory NK cells

Project description:HIV-1 permanently disrupts homeostatic ILCs and expands inflammatory TCF7-dependent memory NK cells

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Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type and mHTT are regulated by a stress-responsive upstream open reading frame, and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

2024-03-13 | PXD026012 | Pride

Small Heterodimer Partner and Fibroblast Growth Factor-19 Inhibit Intestinal Npc1l1 Expression and Cholesterol Absorption

Project description:Small Heterodimer Partner (SHP/NR0B2) is an unusual orphan nuclear receptor that does not have a DNA binding domain and acts as a co-repressor for many transcriptional factors, including LRH-1, SREBPs, FOXA1, and AhR, which inhibits expression of its target genes. To explore global intestinal functions of SHP, WT and SHP-KO mice were fed for 6 h after fasting overnight. In SHP-KO mice, 1,707 genes were upregulated, and 1,055 genes downregulated by 2-fold or more compared to WT mice. In GO analysis, intestinal genes upregulated with the highest significance were involved in the transport of ions, lipids, and hormones, and in cholesterol metabolic processes; whereas genes downregulated were involved in the cell cycle, the immune response, and apoptosis. Remarkably, expression of genes important for cholesterol absorption, including Npc1l1, sterol biosynthetic genes, including Hmgcr, and key intestinal bile acid transporters, Asbt and Ost-alpha/beta, was altered in SHP-KO mice compared to WT mice. Overall, in this study, SHP was shown to be a gene-specific transcriptional partner of SREBP-2 to epigenetically inhibit cholesterol-regulating genes, including Npc1l1, in the late-fed state.

2019-02-23 | GSE126939 | GEO

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