Lipid Droplet-Associated Hydrolase Mobilizes Oxysterol Stores and Inhibits Atheroma Growth and Progression
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ABSTRACT:
PROVIDER: PRJNA663469 | ENA |
REPOSITORIES: ENA
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Project description:Lipid droplets (LDs) of foam cells within atheroma contain abundant cholesterol, but also serve as reservoirs of central bioactive lipids. The mechanisms of storage and mobilization of many of these lipids remain obscure. LD-associated hydrolase (LDAH) localizes to LDs, has a lipase structure, and is abundant in atheroma. However, its lipid substrates and role in atherogenesis are unknown. Using knockout and transgenic mice we found that LDAH protects against atherosclerosis. Myeloid LDAH expression is sufficient to inhibit lesion progression and promote stable architectures, less necrotic, and richer in fibrillar collagen. Lipidomics coupled with RNA sequencing revealed that LDAH facilitates mobilization of esters of oxysterols that are liver X receptor agonists, leading to induction of cholesterol efflux transporters, reduced foam cell inflammation, and pro-fibrotic gene signatures. These studies identify LDAH as a novel player in neutral hydrolysis of esterified regulatory sterols that promotes atheroprotective and pro-stabilizing mechanisms beyond mass cholesterol removal.
2020-11-10 | GSE157947 | GEO
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2017-03-15 | PXD004304 | Pride
Project description:Metabolism of anticancer drugs markedly affects their antitumor effects. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing taxanes and/or anthracyclines with therapy response and survival of breast carcinoma patients The present study investigated transcript levels of key modulators of oxysterol signaling pathway, including oxysterol receptors, metabolic enzymes and transporters in the group of hormone-receptor positive breast carcinoma patients to evaluated potential clinical significance of these genes.
2017-04-06 | GSE85206 | GEO
Project description:Metabolism of anticancer drugs markedly affects their antitumor effects. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing taxanes and/or anthracyclines with therapy response and survival of breast carcinoma patients The present study investigated differences in transcript levels of key modulators of oxysterol signaling pathway, including oxysterol receptors, metabolic enzymes and transporters in the groups of estrogen receptor positive (ER+) breast carcinomas in comparison to estrogen receptor negative (ER-) ones, and to control non-tumor tissues.
2017-04-06 | GSE85207 | GEO
Project description:We report RNA-seq results from planarians of Dugesia japonica species which have developed resistance to a S-adenosyl homocysteine hydrolase inhibitor AdOx after prolonged exposure.
2021-11-01 | GSE155645 | GEO
Project description:Many members of the oxysterol binding protein related protein (ORP) family have been characterized in detail over the past decades, but the lipid transport and other functions of ORP7 still remain elusive. What is known about ORP7 points toward an endoplasmic reticulum and plasma membrane-localized protein, which also interacts with GABARAPL2 and unlipidated LC3B, suggesting a further autophagosomal/lysosomal association. Functional roles of ORP7 have been suggested in cholesterol efflux, hypercholesterolemia, and macroautophagy. We performed a hypothesis-free omics analysis of chemical ORP7 inhibition utilizing transcriptomics and lipidomics as well as proximity biotinylation interactomics to characterize ORP7 functions in a primary cell type, human umbilical vein endothelial cells (HUVECs). Moreover, assays on metrics such as angiogenesis, cholesterol efflux and lipid droplet quantification were conducted. Pharmacological inhibition of ORP7 lead to an increase in gene expression related to lipid metabolism and inflammation, while genes associated with cell cycle and cell division were downregulated. Lipidomic analysis revealed increases in ceramides, lysophosphaditylcholines, as well as saturated and monounsaturated triacylglycerols. Significant decreases were seen in all cholesteryl ester and in some unsaturated triacylglycerol species, compatible with the detected decrease of mean lipid droplet area. Along with the reduced lipid stores, ABCG1-mediated cholesterol efflux and angiogenesis decreased. Interactomics revealed an interaction of ORP7 with AKT1, a central metabolic regulator. The transcriptomics results suggest an increase in prostanoid as well as oxysterol synthesis, which could be related to the observed upregulation of proinflammatory genes. We envision that the defective angiogenesis in HUVECs subjected to ORP7 inhibition could be the result of an unfavorable plasma membrane lipid composition and/or reduced potential for cell division. To conclude, the present study suggests multifaceted functions of ORP7 in lipid homeostasis, angiogenic tube formation and gene expression of lipid metabolism, inflammation and cell cycle in primary endothelial cells.
2024-03-19 | GSE261689 | GEO
Project description:Bacteria synthesize guanosine tetra- and penta phosphate (commonly referred to as (p)ppGpp) in response to environmental stresses. (p)ppGpp reprograms cell physiology and is essential for stress survival, virulence and antibiotic tolerance. Proteins of the RSH superfamily (RelA/SpoT Homologues) are ubiquitously distributed and hydrolyze or synthesize (p)ppGpp. Structural studies have suggested that the shift between hydrolysis and synthesis is governed by conformational antagonism between the two active sites in RSHs. RelA proteins of γ-proteobacteria exclusively synthesize (p)ppGpp and encode an inactive pseudo-hydrolase domain. Escherichia coli RelA synthesizes (p)ppGpp in response to amino acid starvation with cognate uncharged tRNA at the ribosomal A-site, however, mechanistic details to the regulation of the enzymatic activity on the ribosome remain elusive. Here, we show a novel role of the enzymatically inactive hydrolase domain in modulating the activity of the synthetase domain of RelA. Using random mutagenesis screening and functional studies, we identify a loop region (residues 114-130) in the hydrolase domain, which controls the synthetase activity. We show that a synthetase-inactive loop mutant of RelA is not affected for tRNA binding, but binds the ribosome less efficiently than wildtype RelA. Our data provide strong evidence to support the model that the hydrolase domain acts as a molecular switch to regulate the synthetase activity.
2021-03-31 | GSE150416 | GEO
Project description:Sequencing data related to the manuscript entitled, "Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain".
2019-10-30 | GSE139542 | GEO
Project description:Expression of oxysterol pathway genes in estrogen positive breast carcinomas
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Project description:Oxysterol signatures distinguish age-related macular degeneration from physiologic aging
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