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Targeting Epsins by nanotherapy regulates lipid metabolism and promotes ABCG1-mediated cholesterol efflux to fortify atheroma regression [scRNA-seq]

ABSTRACT: Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically-target macrophage Epsins with specially-designed S2P-conjugated lipid nanoparticles (NPs), which encapsulate small interfering RNAs to suppress Epsins.Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.

ORGANISM(S): Mus musculus

PROVIDER: GSE214413 | GEO | 2022/11/26

REPOSITORIES: GEO

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Targeting Epsins by nanotherapy regulates lipid metabolism and promotes ABCG1-mediated cholesterol efflux to fortify atheroma regression [RNA-seq]

Project description:Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically-target macrophage Epsins with specially-designed S2P-conjugated lipid nanoparticles (NPs), which encapsulate small interfering RNAs to suppress Epsins.Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.

2022-11-26 | GSE214412 | GEO

Targeting Epsins by nanotherapy regulates lipid metabolism and promotes ABCG1-mediated cholesterol efflux to fortify atheroma regression.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-26 | GSE214414 | GEO

Cyclodextrin promotes atherosclerosis regression via LXR activation (II)

Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .

2016-05-06 | GSE67013 | GEO

Cyclodextrin promotes atherosclerosis regression via LXR activation (I)

2016-05-06 | GSE67011 | GEO

Intercepting IRE1 Kinase-FMRP Signaling Prevents Atherosclerosis Progression

Project description:Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP-deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggest IRE1 inhibition as a promising new way to counteract atherosclerosis.

2022-02-15 | PXD030594 | Pride

LncRNA/mRNA expression profiling for THP-1 macrophages and THP-1 macrophage-derived foam cells

Project description:By identifying differentially expressed LncRNAs/mRNAs in THP-1 macrophages and THP-1 macrophage-derived foam cells, we select some differentially expressed LncRNAs and explore their roles in atherosclerosis process. We already find that some LncRNA can effect cholesterol metabolism and level of inflammation factor, which may influence atherosclerosis process. In the study presented here, 6 human samples were used to acquire expression profiles, which provide futher insight into the pathologies of atherosclerosis

2014-05-20 | E-GEOD-54039 | biostudies-arrayexpress

Lipid Droplet-Associated Hydrolase Mobilizes Oxysterol Stores and Inhibits Atheroma Growth and Progression

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

Anti-inflammatory effects of HDL in macrophages predominate over pro-inflammatory effects in atherosclerotic plaques

Project description:HDL infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. While some studies have shown anti-inflammatory effects of HDL in macrophages, others have reported pro-inflammatory effects and there is no consensus on underlying mechanisms. Transcriptional profiling reveals that HDL-mediated cholesterol efflux leads to both pro- and anti-inflammatory effects in LPS-stimulated macrophages. While early anti-inflammatory effects reflect reduced TLR4 levels, late anti-inflammatory effects are due to reduced interferon receptor signaling. Pro-inflammatory effects occur late and are ER stress responses mediated by IRE1a/ASK1/p38 MAPK signaling under conditions of marked cholesterol depletion. rHDL infusions in hypercholesterolemic atherosclerotic mice produced moderate anti-inflammatory effects in lesional macrophages without pro-inflammatory gene expression changes suggesting a beneficial therapeutic effect of HDL in vivo.

2020-04-04 | GSE129347 | GEO

Adrenal Abcg1 controls cholesterol flux and steroidogenesis

Project description:Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its systemic inactivation results in neutral lipid redistribution to macrophages. However, the function of ABCG1 in steroidogenic organs is not explored. To model this question, we inactivated the ortholog Abcg1 gene in the mouse adrenal cortex. Abcg1 disruption led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis, and to an 80% increase in corticosterone production. Importantly, this phenotype was not recapitulated by inactivation of the cholesterol exporter Abca1. The absence of any change in lipid profile suggested that adrenal Abcg1 is not involved in cholesterol export to a clinically relevant extent.

2023-09-05 | GSE242081 | GEO

LncRNA/mRNA expression profiling for THP-1 macrophages and THP-1 macrophage-derived foam cells

2014-05-20 | GSE54039 | GEO

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