Endothelial Cell CD36 Optimizes Tissue Fatty Acid Uptake
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA478230 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7443480.fastq.gz | Fastqsanger.gz | |||
| SRR7443490.fastq.gz | Fastqsanger.gz | |||
| SRR7443481.fastq.gz | Fastqsanger.gz | |||
| SRR7443491.fastq.gz | Fastqsanger.gz | |||
| SRR7443482.fastq.gz | Fastqsanger.gz |
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Project description:Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multi-ligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that CD36-mediated FA transport across ECs rate-limits tissue FA uptake, and its loss leads to metabolic effects in parenchymal cells.
2018-06-28 | GSE116350 | GEO
Project description:Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.
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Project description:Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examined how ECs transfer FAs. FA interaction with apical membrane CD36 induced Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Fission of the caveolae yielded vesicles containing FAs, CD36 and ceramide that were secreted basolaterally as small (80-100nm) exosome-like extracellular vesicles (sEVs). We visualized EC transfer of FAs in sEVs to underlying myotubes in transwells. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulated circulating FAs in emGFP-labeled puncta. The FA-sEV pathway was mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduced muscle FA uptake, raised circulating FAs, which remained in blood vessels, and lowered glucose, mimicking prominent Cd36-/- phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
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Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
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Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
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Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behavior. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
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Project description:Controlling fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid rafts, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion, as well as fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diets exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen if feeding the transgenic animals with regular diets. Inhibitions of stomatin by gene knockdown or OB-1 pharmacological treatments inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involve ERK signaling; however, an alternate pathway may also exist. Differential expression analyses by microarray were performed comparing stomatin-knockdown and control 3T3-L1 adipocyte-like cells.
2022-05-28 | GSE205011 | GEO
Project description:Controlling fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid rafts, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion, as well as fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diets exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen if feeding the transgenic animals with regular diets. Inhibitions of stomatin by gene knockdown or OB-1 pharmacological treatments inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involve ERK signaling; however, an alternate pathway may also exist.
2022-07-05 | PXD031866 | Pride
Project description:Metastasis is the leading cause of cancer-related deaths. For most human cancers, the identity of the cells that initiate and promote metastasis is still unknown, hampering our ability to develop therapies to prevent or inhibit the spread of tumour cells to distant sites. Using an orthotopic model of human oral squamous cell carcinoma (OSCC), we have now identified a subpopulation of CD44bright cells within the primary lesion with the highest potential to develop lymph node and lung metastasis. This population is slow-cycling, expresses high levels of the receptor CD36 at the cell membrane and relies on fatty acid metabolism to thrive in lymph nodes and bronchoalveolar environments. Importantly, inhibition of CD36 by either shRNA or neutralizing monoclonal antibodies severely impairs metastatic spread of primary OSCC patient samples and established cell lines. Further underscoring its importance, CD36 overexpression in poorly disseminating tumours confers an aggressive metastatic behaviour. Analyses of public gene expression data indicate that the presence of the signature-defining CD36+ cells also strongly correlates with a poor prognosis in patients with lung SCC, ovarian cancer, bladder cancer, or luminal breast cancer. By identifying metastasis-promoting cells and then targeting them with CD36 inhibition, novel anti-metastatic therapies could be developed for patients with these types of tumours.
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