Esculetin promotes HDL-driven cholesterol excretion involved in CD36-mediated phagocytosis of adipose tissue macrophages and CEBPbeta
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ABSTRACT:
PROVIDER: PRJNA982877 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24902304_1.fastq.gz | Fastqsanger.gz | |||
| SRR24902304_2.fastq.gz | Fastqsanger.gz | |||
| SRR24902305_1.fastq.gz | Fastqsanger.gz | |||
| SRR24902305_2.fastq.gz | Fastqsanger.gz | |||
| SRR24902306_1.fastq.gz | Fastqsanger.gz |
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Project description:Postprandial dyslipidemia is a recognized risk factor for atherosclerosis. High-density lipoprotein (HDL)-mediated reverse cholesterol transport plays a crucial role in mitigating this risk by clearing postprandial lipids. This study aimed to investigate the impact of esculetin, a 4-Hydroxycoumarin, on postprandial cholesterol metabolism and excretion after a high-fat meal. Esculetin significantly elevated postprandial HDL cholesterol levels in serum and postprandial bile acid levels in bile, and altered serum metabolomics in mice fed a high-fat meal, indicating esculetin promotes HDL-driven cholesterol excretion after a high-fat meal. Furthermore, esculetin administration in mice led to an increase in the ratio and phagocytic activity of a subset of adipose tissue macrophages (ATMs) expressing high levels of CD36 and Tim4. Inhibition of CD36 by Sulfo-N-succinimidyl oleate (SSO) blocked esculetin-induced elevation of postprandial serum HDL and bile acid levels in bile. Additionally, esculetin demonstrated the ability to increase the uptake of oxidized LDL (ox-LDL) via CD36 in a macrophage cell line, which might involve alteration of the epigenetic landscape controlled by CCAAT enhancer-binding protein beta (C/EBPβ). Esculetin-induced increased uptake of ox-LDL and elevation of CD36 was inhibited in C/EBPβ-deficient cells. A relatively higher expression of C/EBPβ was observed in CD36+ ATMs, and esculetin increased the ratio of C/EBPβ+ CD36+ ATMs in mice fed a lipid-rich meal. Moreover, the direct interaction between esculetin and C/EBPβ were observed by Terahertz chemical microscope. Overall, these findings suggest esculetin promotes HDL-mediated postprandial cholesterol excretion by directly binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
2024-06-12 | GSE234771 | GEO
Project description:Intake and absorption of cholesterol (the latter determined by double labeled cholesterol methodology) were nearly unchanged in mice fed the saturated fat diet, but the fecal excretion of neutral sterols (i.e. cholesterol and its microbial conversion products) was increased compared with control diet(+80%; p<0.01). The saturated fat diet did neither significantly affect biliary cholesterol secretion nor intestinal cholesterol absorption (49% vs. 65% in controls, double labeled water methodology, p>0.1). Thus, the increased fecal neutral sterol excretion was primarily due to increased net transintestinal cholesterol excretion (+89% versus control; p<0.05). Since a major fraction of TICE cholesterol absorption is normally reabsorbed (J Lipid Res 2019 Sep;60(9):1562-1572), the increased fecal cholesterol excretion could be due to more transintestinal excretion of cholesterol into the intestinal lumen and/or to its decreased reabsorption. The saturated fat diet increased jejunal expression of genes involved in cholesterol synthesis (Srebf2 and target genes), but did not affect whole body de novo cholesterol synthesis. Conclusion This proof-of-principle study shows that increasing the saturation of the dietary fat can stimulate fecal cholesterol excretion. Individual components of saturated fat diets are to be explored to address the responsible molecular mechanisms
2021-02-01 | GSE37097 | GEO
Project description:Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we reveal that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborate that SELENOK deficiency inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in the brains of AD patients and mice. Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.
2024-02-29 | GSE255034 | GEO
Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .
2012-06-30 | E-GEOD-37902 | biostudies-arrayexpress
Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3′ splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism.
2012-07-01 | GSE37902 | GEO
Project description:ABSTRACT Background & aims: The role of the intestine in the maintenance of cholesterol homeostasis is increasingly recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport (RCT) pathway, to which both biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway are,however, poorly understood. In the current study we aimed to identify treatment modalities that stimulate TICE and to uncover underlying driving mechanisms. Methods: TICE was assessed in a panel of knock-out and transgenic mice as well as in mice treated with the FXR agonist PX20606 either or not combined with the cholesterol absorption inhibitor ezetimibe. Results: We show that TICE is regulated by intestinal farnesoid X receptor (FXR) via its target fibroblast growth factor 15/19 (FGF15/19) and that the pathway can be stimulated to such an extent that mice excrete ~60% of their total cholesterol content each day. Both PX20606 and FGF19 increased the muricholate/cholate ratio in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool robustly stimulated secretion of cholesterol into the intestinal lumen via the sterol exporting heterodimer ATP binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, we demonstrate that the increase in TICE induced by PX20206 is independent of changes in cholesterol absorption. Conclusions: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Translation of these results to humans may offer new treatment modalities for prevention of cardiovascular disease.
2017-01-10 | GSE74101 | GEO
Project description:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of these pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4-weeks treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile-derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a fourfold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.
2016-11-04 | GSE77236 | GEO
Project description:Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis. We used microarrays to detail the global programme of gene expression affected by FGF19 treatment in mice.
2019-01-25 | GSE117855 | GEO
Project description:Specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis. Carriers do not exhibit increased cardiovascular disease risk despite reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of L75P and L174S patients presents a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.
2020-11-20 | PXD021266 | Pride
Project description:SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis
| PRJNA1073397 | ENA