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Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

ABSTRACT: To evaluate gene expression changes in response to low-density-lipoprotein related protein 1 (LRP1) depletion in endothelial cells, we performed mRNA-sequencing analysis with microvascular endothelial cells isolated from the liver LRP1 endothelial knockout mice and their littermate control wild type mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE117555 | GEO | 2021/06/11

REPOSITORIES: GEO

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Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

Project description:To evaluate gene expression changes in response to low-density-lipoprotein related protein 1 (LRP1) depletion in endothelial cells, we performed mRNA-sequencing analysis with microvascular endothelial cells isolated from the lung, heart and liver LRP1 endothelial knockout mice and their littermate control wild type mice.

2021-06-11 | GSE117554 | GEO

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

| PRJNA482452 | ENA

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

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

2021-06-11 | GSE117560 | GEO

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

| PRJNA482455 | ENA

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

| PRJNA482461 | ENA

Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.

Project description:The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.

| S-EPMC8421392 | biostudies-literature

Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression

Project description:In the present study, we analyzed single-cell multi-omics data from psoriasis patients and healthy individuals and found that more fibroblast-macrophage communication was present in the dermis of psoriasis lesions, exacerbating psoriasis progression. A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells. Moreover, conditional knockdown of LRP1 by fibroblasts significantly improved psoriasis in mice, suggesting that LRP1 may be an important target for the treatment of psoriasis.

2024-03-31 | GSE230842 | GEO

Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression

Project description:Purpose: This study aimed to explore the mechanism of Celastrol in improving psoriasis through single-cell transcriptomics Methods: Supplementation with intragastric administration of celastrol in C57BL/6 mice to observe its effect on IMQ-induced psoriasis. Single-cell RNA sequencing were performed to explore the role of celastrol for IMQ-induced psoriasis. Results: A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells Conclusion: We report that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages. The use of celastrol maybe a noveltherapeuticoption for psoriasis.

2024-04-20 | GSE231728 | GEO

LRP1 in Vascular Remodeling and Angiotensin Signaling

Project description:Vascular smooth muscle cells (vSMC) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor-related protein 1 (LRP1), a large endocytic and signaling receptor that recognizes numerous ligands including ApoE-rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in v SMC (smLRP1-/- mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1-/- mice that are known to be induced by angiotensin II (AngII)-mediated signaling, suggesting that this pathway is dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1-/- mice and prevented aneurysm formation. Additionally, employing a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1-/- mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.

2023-03-11 | PXD038236 | Pride

EDEM3 modulates plasma triglyceride level through its regulation of LRP1 expression

Project description:Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases and metabolic conditions. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and ER protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals with carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.

2020-03-30 | GSE146070 | GEO

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