Fatty Acid Uptake in T Cell Subsets Using a Quantum Dot Fatty Acid Conjugate

Muroski, Megan E.; Miska, Jason; Chang, Alan L.; Zhang, Peng; Rashidi, Aida; Moore, H. C.; Lopez-Rosas, Aurora; Han, Yu; Lesniak, Maciej S.

doi:10.1038/s41598-017-05556-x

Cited by 29 publications

(31 citation statements)

References 34 publications

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“…As proof of principle, we first determined whether naïve T cells can endocytose TAG from lipoproteins and whether this is inhibited by apoC-III. Previous studies have used fatty acids bound to BSA or DMSO, or have addressed the impact of oxidized lipids from LDL and HDL on immune cells [36][37][38]. First, we confirmed the expression of LDLr in Jurkat T cells, our model for parent T cells, after treating them with TRLs containing varying amounts of apoC-III (Supplementary Figure 7).…”

Section: Tregs Express Lipid Transporters and Apoc-iii Can Inhibit Tsupporting

confidence: 66%

“…Tregs oxidize exogenous free fatty acids (palmitate), and the blockage of glycolysis, lack of exogenous glucose, or excess palmitate in the media will result in Treg enrichment, suppressive activity, and differentiation from CD4 + precursors[21, 22,42,43]. In addition, ex vivo Tregs will take up exogenous FFAs at a greater rate when they are rapidly proliferating, and during activation [37,44]. Though these studies are critical to understanding how Tregs response to metabolic cues, they share the limitation that Tregs in vivo are normally exposed to triglyceride, not palmitate, in lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

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ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Rodia

Tambini

et al. 2019

Preprint

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Objective: Cellular metabolism is a key regulator of CD4 + Foxp3 + regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids. Design/Results: Using apolipoprotein C-III transgenic and LDLr -/mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipytriglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis. Conclusion: Our data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine. Summary Box * What is already known about this subject:§ The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation. § ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways § ApoC-III is reduced in Crohn's and Colitis patients. * What are the new findings:§ We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes. § We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III. § Tregs from apoC-III Tg are metabolically unique from WT Tregs and they upregulate the genes of lipolysis, and have an increase in basal respiration. § The inhibition of TAG endocytosis, using 2 different models (LDLr KO and apoC-IIItransgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut. § Intraperitoneal delivery of apoC-III on chylomicrons protects WT mice from DSS colitis. * How might it impact on clinical practice in the foreseeable future?§ Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.the TAG for fuel through two processes: the hydrolysis of TAG to free fatty acids (FFA) via membrane-bound lipoprotein lipase (LPL) and the subsequent transport of those FFAs into the cell, or alternatively, endocytosis of lipoprotein TAG via the low-density lipoprotein receptor (LDLr), and the subsequent intracellular hydrolysis, oxidation, or storage of those FFAs. The way that a cell encounters a lipid fuel (either as a FFA bound to albumin or as a holoparticle lipoprotein) as sign...

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Section: Tregs Express Lipid Transporters and Apoc-iii Can Inhibit Tsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Rodia

Tambini

et al. 2019

Preprint

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“…Other lymphoid cells such as Treg cells are enriched in peripheral adipose tissues . Similar to ILC2, these cells strongly depend on FAO as their primary energy source independent of de novo fatty acid synthesis and mostly reliant on the import of fatty acids from the environment . Adipose Treg cells are induced upon several metabolic and environmental stimuli and have been suggested to control adipocyte function through a signal transducer and activator of transcription 6–phosphatase and tensin homologue axis .…”

Section: Fatty Acids In the Bone Marrow To Support Long‐lived Immunementioning

confidence: 99%

“…30 Similar to ILC2, these cells strongly depend on FAO as their primary energy source independent of de novo fatty acid synthesis and mostly reliant on the import of fatty acids from the environment. [31][32][33] Adipose Treg cells are induced upon several metabolic and environmental stimuli and have been suggested to control adipocyte function through a signal transducer and activator of transcription 6-phosphatase and tensin homologue axis. 34 On the other hand, adipocytes can regulate T-cell fate through major histocompatibility complex class II-dependent secretion of interferon-c. 35 However, the regulation of adipose-derived metabolites of T-cell differentiation remains largely unanswered.…”

Section: Fatty Acids In the Bone Marrow To Support Long-lived Immunementioning

confidence: 99%

Local exchange of metabolites shapes immunity

2018

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SummaryImmune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge.

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“…We therefore sought to determine if activation of DRD2 does in fact lead to GBM39-specific alterations in metabolism. First, we analyzed the uptake of glucose and fatty acid via FACS, utilizing 2-NBDG, a well-established fluorescent analog of glucose, and our proprietary fatty-acid tagged quantum dots (Muroski et al 2017). Only GBM39 showed altered fatty acid uptake following DRD2 activation.…”

Section: Activation Of Drd2 Induces Alterations In Expression Of Hif-mentioning

confidence: 99%

Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma

Caragher

Shireman²,

Huang³

et al. 2018

Preprint

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Glioblastoma (GBM) is one of the most aggressive and lethal tumor types. Evidence continues to accrue indicating that the complex relationship between GBM and the brain microenvironment contributes to this malignant phenotype. However, the interaction between GBM and neurotransmitters, signaling molecules involved in neuronal communication, remains incompletely understood. Here we examined, in both sexes of humans and mice, how the monoamine dopamine influences GBM cells. We demonstrate that GBM cells express DRD2, with elevated expression in the glioma-initiating cell (GIC) population. Stimulation of DRD2 caused neuron-like depolarization exclusively in GICs. In addition, long-term activation of DRD2 heightened the sphere-forming capacity of GBM cells as well as tumor engraftment efficiency. Mechanistic investigation revealed that DRD2 signaling activates the hypoxia response and functionally alters metabolism. Finally, we found that GBM cells synthesize and secrete dopamine themselves, suggesting a potential autocrine mechanism. These results identify dopamine signaling as a potential therapeutic target in GBM and further highlight neurotransmitters as a key feature of the pro-tumor microenvironment. Significance Statement:This work offers critical insight into the role of the neurotransmitter dopamine in the progression of GBM. We show that dopamine induces specific changes in the state of tumor cells, augmenting their growth and shifting them to a more stem-cell like state. Further, we show that dopamine can alter the metabolic behavior of GBM cells, increasing glycolysis. Finally, we show that GBM cells, including tumor samples from patients, can synthesize and secrete dopamine, suggesting an autocrine signaling process underlying these results. These results describe a novel connection between neurotransmitters and brain cancer, further highlighting the critical influence of the brain milieu on GBM. 4.Olmez I, Shen W, McDonald H, Ozpolat B. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogenindependent growth.

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Fatty Acid Uptake in T Cell Subsets Using a Quantum Dot Fatty Acid Conjugate

Cited by 29 publications

References 34 publications

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Local exchange of metabolites shapes immunity

Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma

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