Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA1031630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26499880.fastq.gz | Fastqsanger.gz | |||
| SRR26499881.fastq.gz | Fastqsanger.gz |
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Project description:Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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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: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 elevation of ApoB-containing lipoproteins causes 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 (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.
| S-EPMC10866653 | biostudies-literature
Project description:Desmosterol suppresses inflammasome activation and protects against atherosclerosis
| PRJNA723043 | ENA
Project description:Desmosterol suppresses inflammasome activation and protects against atherosclerosis II
| PRJNA732064 | 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.
2021-12-31 | GSE172374 | 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.
2021-12-01 | GSE175312 | GEO
Project description:Background and Aims Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular disease (ASCVD). Although some lipid-lowering drugs have demonstrated positive effects in patients with ASCVD, their effects are limited in those with homozygous familial hypercholesterolemia (HoFH). It is essential to seek new lipid-lowering targets. Yes-associated protein (YAP) may be involved in lipid metabolism in liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Methods Hyperlipidemia models were generated in apoE-/- mice or mice injected with AAV8-D377Y-mPCSK9, which degrades and deletes low density lipoprotein receptor (LDLR), by being fed a high cholesterol diet (HCD) for 12 weeks. We measured the expression level of hepatic YAP in these apoE-/- mice. Next, we created YAPΔHep apoE-/- mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 cells and mice injected with AAV8-D377Y-mPCSK9 or YAPΔHepapoE-/- mice were used to elucidate its mechanism. Finally, apoE-/- or LDLR-/- mice were used to observe the therapeutic efficacy of AAV8-Alb-shYAP for hyperlipidemia and atherosclerosis. Results HCD-fed apoE-/- mice showed increased levels of YAP in the liver. Further investigation indicated that YAPΔHepapoE-/- mice exhibited lighter hyperlipidemia and atherosclerosis than YAPflox/floxapoE-/- mice fed with HCD. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in HCD-fed apoE-/- mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of angiopoietin-like-3 (ANGPTL3) aggravated hyperlipidemia and atherosclerosis in YAPΔHepapoE-/- mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD4 in hepatocytes independent of LDLR. Notably, AAV8-Alb-shYAP lowered lipid levels in apoE-/- or LDLR-/- mice. Conclusion Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for HoFH.
2026-01-20 | GSE316646 | GEO
Project description:Vascular Smooth Muscle Cell-derived KIF13B Protects Against Atherosclerosis: Evidence from Humans and Mice
| PRJNA1392904 | ENA