Desmosterol suppresses inflammasome activation and protects against atherosclerosis II
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ABSTRACT:
PROVIDER: PRJNA732064 | ENA |
REPOSITORIES: ENA
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Project description:Desmosterol suppresses inflammasome activation and protects against atherosclerosis
| PRJNA723043 | ENA
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-01 | GSE175312 | GEO
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-31 | GSE172374 | GEO
Project description:Stress granule and inflammasome assembly determine contrasting fates of stressed cells. FAM69C is a brain-enriched kinase associated with neurodegenerative diseases, but its biological functions are still largely unknown. Here we show that FAM69C plays an important role in the regulation of stress responses through promoting stress granule assembly and suppressing inflammasome activation. In response to ATP, a common inflammasome activator, mouse primary microglia, and BV-2 cells form stress granules. FAM69C deficiency hastens inflammasome activation in mouse microglia, which is accompanied by inhibited stress granule assembly. FAM69C promotes the assembly of stress granules and halts protein translation under stress. Aged Fam69c knockout mice show increased neuroinflammation and ASC specks formation. We further find that FAM69C physically phosphorylates eIF2α and promotes stress granule assembly. Our data reveal that FAM69C promotes stress granule assembly under stress and suppresses inflammasome formation in microglia, suggesting that FAM69C may be a potential therapeutic target for neurodegenerative diseases.
2022-10-05 | GSE214646 | GEO
Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
2023-12-07 | GSE246083 | GEO
Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
2023-10-31 | GSE246138 | GEO
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
Project description:DAG-activated Pkd1 promotes triglyceride accumulation in adipocytes; Pkd1 promotes lipogenesis and suppresses mitochondrial function in adipocytes in an AMPK-dependent manner; Pkd1 suppresses expression of genes characteristic for beige adipocytes; Deletion of Pkd1 in adipocytes protects mice from diet-induced obesity, T2D and liver steatosis.
2018-09-20 | GSE104797 | GEO
Project description: Not available
| S-EPMC3567828 | biostudies-other
Project description:Inflammasomes are multiprotein platforms of caspase-1 activation. The NLRP3 inflammasome is composed of NLRP3, ASC, and procaspase-1. This inflammasome is activated by various endogenous and exogenous stimuli, including pneumococci, and protects from a variety of microbial pathogens. In the present study, we examined the role of NLRP3 inflammasome components in gene expression in the lung during pneumococcal pneumina.
2014-12-31 | GSE56653 | GEO