Effects of deletioin of cholesterol efflux genes Abca1 and Abcg1 on other gene expressions in macrophages
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PROVIDER: PRJNA981554 | ENA |
REPOSITORIES: ENA
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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: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.
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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 | GSE214413 | GEO
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
Project description:ATP binding cassette transporter A1 (ABCA1) regulates cellular cholesterol efflux. We characterized the gene expression changes following hepatocyte specific ABCA1 deletion in mice. We report that genes and pathways related to lipogenesis were downregulated in mice with hepatocyte specific ABCA1 deletion compared to floxed controls.
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Project description:Adrenal Abcg1 controls cholesterol flux and steroidogenesis
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Project description:Targeting Epsins by nanotherapy regulates lipid metabolism and promotes ABCG1-mediated cholesterol efflux to fortify atheroma regression.
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Project description:Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naïve mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia nor reversed CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
2021-04-16 | GSE154816 | GEO
Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXRdependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis
2018-01-26 | GSE98910 | GEO
Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis.
2018-01-26 | GSE97207 | GEO