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VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [HBMEC]

ABSTRACT: VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [HBMEC]

PROVIDER: PRJNA609314 | ENA |

REPOSITORIES: ENA

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VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading

Project description:VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading

| PRJNA609312 | ENA

VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [HBMEC]

Project description:Regulation of endothelial nutrient transport is poorly understood. Vascular endothelial growth factor (VEGF)-B signaling in endothelial cells promotes uptake and transcytosis of fatty acids (FA) from the bloodstream to the underlying tissue, advancing pathological lipid accumulation and lipotoxicity in diabetic complications. Here we demonstrate a VEGF-B dependent obstruction of endothelial glucose transport attributed to plasma membrane lipid alterations affecting glucose transporter 1 function, which was independent of FA uptake. Specifically, VEGF-B signaling impaired recycling of low-density lipoprotein receptor to the plasma membrane, leading to reduced cholesterol uptake and membrane cholesterol loading, decreasing endothelial glucose uptake capacity. Inhibiting VEGF-B in vivo was accordingly linked to reconstitution of membrane cholesterol and induction of glucose uptake, of particular relevance for conditions inferring insulin resistance and diabetic complications. In summary, our study reveals a novel mechanism of action for VEGF-B in endothelial nutrient uptake and highlights the impact of membrane cholesterol for the regulation of endothelial glucose transport.

2020-04-06 | GSE146108 | GEO

VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [mouse heart]

2020-04-06 | GSE146107 | GEO

VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [mouse heart]

Project description:VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading [mouse heart]

| PRJNA609315 | ENA

VEGF-B Signaling Impairs Endothelial Glucose Transcytosis via an LDLR-dependent Decrease in Membrane Cholesterol Loading

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-06 | GSE146109 | GEO

VEGF-D deficiency causes hyperlipidemia and delayed clearance of chylomicron remnants

Project description:Objective: Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of Vascular Endothelial Growth Factor (VEGF) family to lipid metabolism but the function of VEGF-D has remained unexplored. Here we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/-ApoB100/100 mice. Approach and Results: Deletion of VEGF-D (Vegfd-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of syndecan 1 (SDC1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGF receptor 3 led to lowered expression of genes regulating triglyceride and cholesterol production as well as downregulation of peroxisomal β-oxidation pathway. Conclusions: These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.

2018-08-16 | GSE108959 | GEO

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

Project description:PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI- 8 raises by 80 % the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high cholesterol feeding, or by E2 known to stimulate cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80 % lower circulating LDL.

2022-09-22 | GSE205008 | GEO

Single-nucleus RNA-seq of aortas from Ldlr-/- and Ldlr-/-Trem2-/- atherosclerotic mice

Project description:Single-nucleus RNA-seq of aortas was performed in Ldlr-/- and Ldlr-/-Trem2-/- mice fed a high fat diet for 10 weeks

2024-01-12 | GSE243086 | GEO

Bulk RNA-sequencing in Ldlr-/- or Ch25h-/-;Ldlr-/- peritoneal macrophages treated with LPS

Project description:Here we study the effect of LPS in the transcriptome of thioglycollate-elicited peritoneal macrophages isolated from Ldlr knock out and Ch25h;Ldlr double knock out mice

2022-07-01 | GSE189079 | GEO

Liver gene expression profiles of Tribbles-homolog1 (Trib1)/Ldl-receptor (Ldlr) double-knockout mice against Ldlr-knockout mice

Project description:Genetic variants at the TRIB1 (Tribbles-homolog 1) gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. In this study, we analyzed the consequences of Trib1-deficiency (Trib1-/-) on hepatic gene expression in mice on the atherosclerosis-susceptible LDL-receptor deficient (Ldlr-/-) background. Therefore, Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol, 4.3% fat). At 20 weeks of age, Trib1-/-Ldlr-/- mice and Trib1+/+Ldlr-/- control mice were sacrificed and liver tissue was snap frozen in liquid nitrogen and stored at -80°C until further processing. Total RNA was isolated from liver tissue (n=8 mice per genotype) and subjected to microarray gene expression analysis.

2023-03-15 | E-MTAB-12669 | biostudies-arrayexpress

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