Nimbolide competitively binds to 14-3-3 epsilon with TFEB to promote lipophagy and ameliorate atherosclerosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325316 | GEO | 2026/03/24
REPOSITORIES: GEO
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Project description:Nimbolide competitively binds to 14-3-3 epsilon with TFEB to promote lipophagy and ameliorate atherosclerosis
| PRJNA1439632 | ENA
Project description:Background: Atherosclerosis is a chronic inflammatory disease driven by macrophages. PKCɛ (protein kinase C epsilon) is a serine/threonine kinase involved in diverse cellular processes including migration, growth, differentiation, and survival. PKCɛ acts in a context-dependent manner within the heart; however, its role in atherosclerosis is unknown. Methods: Bone marrow-derived macrophages from global PKCɛ knockout mice were tested for lipid retention and cytokine secretion. Public gene set analysis assessed raw counts of PRKCE in human atheromas to determine translational relevance. A LysM Cre PKCɛfl/fl (myeloid-selective PKCɛ knockout [mɛKO]) mouse was developed to study the impact of myeloid PKCɛ on atherosclerosis. After confirming myeloid-selective PKCɛ deletion, human-like hypercholesterolemia was induced, and multiple metrics of atherosclerosis were compared in wild-type (WT) and mɛKO plaques. RNA sequencing was used to provide unbiased insight into possible mechanisms by which PKCɛ regulates atherosclerosis. Results: Public gene set analysis of human atherosclerotic plaque tissue revealed that PKCɛ expression is inversely correlated with plaque vulnerability. Similarly, peritoneal macrophages from WT hypercholesterolemic mice have significantly lower PKCɛ expression, providing a translational rationale for the generation of the mɛKO mouse. Quantitative polymerase chain reaction revealed no differences between genotypes in the expression of genes related to atherosclerosis, at either steady state or on lipid loading, suggesting that loss of PKCɛ does not fundamentally change the basal state and that differences seen are a result of a more complex pathway. Comparing descending aorta and aortic root plaques from WT and mɛKO hypercholesterolemic mice revealed that mɛKO plaques are larger, have larger foam cells and regions of necrosis, and thinner collagen caps. On lipid loading in vitro and in vivo, mɛKO macrophages retained significantly more cholesterol and lipid droplets than WT; Gene Ontology suggests higher expression of genes related to endocytosis in mɛKO macrophages compared with WT. Conclusions: PKCɛ expression is decreased in vulnerable human plaques and decreases in mouse macrophages on lipid loading. mɛKO plaques are larger and exhibit markers of vulnerability. With no differences in SR (scavenger receptor) expression, the impact of PKCɛ deletion is more subtle than simple SR dysregulation. RNA sequencing implicates higher expression of genes involved in endocytosis, and mɛKO macrophages have significantly more lipid-containing endosomes. The data define the atherophenotype of mɛKO mice and demonstrate that PKCɛ restricts lipid uptake into macrophages by a mechanism independent of SR expression. Taken together, these studies identify PKCɛ as a novel atheroprotective gene, laying the foundation for mechanistic studies on the endocytic signaling networks responsible for the phenotype.
2025-07-28 | GSE291828 | GEO
Project description:Formation of foam cell macrophages (FCMs), which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages (NFMs) that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-? action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-? family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells. Samples (n=4/group): Foam cell macrophages (FCM) isolated from inflammatory sponges placed in ApoE null mice fed a high-fat diet (n=4), non-foamy macrophages (NFM) isolated from inflammatory sponges placed in control mice fed a normal diet (n=4).
2015-07-23 | E-GEOD-70126 | biostudies-arrayexpress
Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
2025-06-11 | PXD064538 | Pride
Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
2025-06-11 | PXD064532 | Pride
Project description:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator. In this specific microarray experiment, we studied the effect of genetic knockout of ATF3 on the transcriptional response of macrophages to oxLDL. Murine bone marrow-derived macrophages from two different mouse strains (Atf3-/- and WT) were incubated in the presence or absence of oxidized low-density lipoprotein (oxLDL), and then transcriptionally profiled using the Affymetrix Mouse Exon Array 1.0 ST. The goal was to study the pattern of differential expression between WT and Atf3-/- strains, in oxLDL-induced foam cells and in non-foamy control cells, to identify cellular pathways that may be dysregulated under loss of the transcription factor ATF3 in macrophage foam cells.
2012-03-23 | GSE32358 | GEO
Project description:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator. In this specific microarray experiment, we studied the effect of genetic knockout of ATF3 on the transcriptional response of macrophages to oxLDL. Murine bone marrow-derived macrophages from two different mouse strains (Atf3-/- and WT) were incubated in the presence or absence of oxidized low-density lipoprotein (oxLDL), and then transcriptionally profiled using the Affymetrix Mouse Exon Array 1.0 ST. The goal was to study the pattern of differential expression between WT and Atf3-/- strains, in oxLDL-induced foam cells and in non-foamy control cells, to identify cellular pathways that may be dysregulated under loss of the transcription factor ATF3 in macrophage foam cells. Twelve female mice (six Atf3-/-, and six WT control mice) were sacrificed at 8-12 weeks of age, and macrophages were derived from the femoral bone marrow using rhM-CSF. oxLDL was introduced into the medium for six samples (3 WT and 3 Atf3-/-) at 25 ug/mL on day seven, and after 24 h of incubation, RNA was isolated using Trizol. Labeled cRNA derived from the RNA samples was hybridized to Affymetrix Mouse Exon Array 1.0 ST GeneChips. Microarray data were processed using transcript-level probesets, and are in log2 scale.
2012-03-23 | E-GEOD-32358 | biostudies-arrayexpress
Project description:Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury and that the proatherogenicity of ADAMTS7, a secreted protein, is due to its catalytic activity. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type is insufficient to reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and decreased fibrous cap formation. RNA-sequencing in SMCs revealed an upregulation of lipid uptake genes typically assigned to macrophages. Subsequent experiments demonstrated that ADAMTS7 increases SMC oxLDL uptake through increased CD36 levels. Furthermore, Cd36 expression is increased due to increased levels of PU.1, a transcription factor typically associated with myeloid fate determination. In summary, Adamts7 expression in either SMCs or ECs promotes SMC foam cell formation and atherosclerosis. In SMCs, ADAMTS7 promotes oxLDL uptake via increased PU.1 and Cd36 expression, thereby increasing SMC foam cell formation and atherosclerosis.
2026-01-16 | GSE316135 | GEO
Project description:Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor-15/19 (FGF15/19). Further, postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding-induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta-mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophgay genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19-activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.
| S-SCDT-EMBOJ-2021-109997 | biostudies-other
Project description:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator. In this specific microarray study, we re-analyzed a subset of the data from a 2006 microarray experiment (Gilchrist et al., Nature, 441:173-178, 2006) in which wild-type and Atf3-/- murine macrophages were stimulated with LPS. The goal of this analysis was to identify genes whose LPS responses are significantly affected by loss of ATF3 in macrophages, using up-to-date genome annotations.
2012-03-23 | GSE32574 | GEO