Profiling the expression of fatty acid-binding proteins and fatty acid transporters in mouse microglia and assessing their role in docosahexaenoic acid-d5 uptake

Low, Yi Ling; Pan, Yijun; Short, Jennifer Lynn; Nicolazzo, Joseph A.

doi:10.1016/j.plefa.2021.102303

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…Conversely, the differential effects of lipotoxic SFAs and lipoprotective UFAs may depend on their uptake or arise intracellularly. Among the FA transporters reported to facilitate FA uptake, CD36 is highly expressed in primary mouse microglia cells and BV2 microglia [21]. After being transported into cells, FFAs are converted into fatty acyl-CoAs, which may then be catabolized to generate energy or anabolized to produce a range of molecules, including second messengers, hormones, and diacylglycerols (DAGs).…”

Section: Introductionmentioning

confidence: 99%

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

Urso

Zhou

2021

IJMS

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Obesity and metabolic syndrome are associated with cognitive decline and dementia. Palmitic acid (PA) is increased in the cerebrospinal fluid of obese patients with cognitive impairment. This study was therefore designed to examine fatty acid (FA) lipotoxicity in BV2 microglia cells. We found that PA induced time- and dose-dependent decrease in cell viability and increase in cell death without affecting the cell cycle profile and that PA lipotoxicity did not depend on cell surface free fatty acid receptors but rather on FA uptake. Treatment with sulfosuccinimidyl oleate (SSO), an irreversible inhibitor of fatty acid translocase CD36, significantly inhibited FA uptake in BSA- and PA-treated cells and blocked PA-induced decrease in cell viability. Inhibition of ER stress or treatment with N-acetylcysteine was not able to rescue PA lipotoxicity. Our study also showed that unsaturated fatty acids (UFAs), such as linoleic acid (LA), oleic acid (OA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), were not lipotoxic but instead protected microglia against PA-induced decrease in cell viability. Co-treatment of PA with LA, OA, and DHA significantly inhibited FA uptake in PA-treated cells. All UFAs tested induced the incorporation of FAs into and the amount of neutral lipids, while PA did not significantly affect the amount of neutral lipids compared with BSA control.

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Section: Introductionmentioning

confidence: 99%

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

Urso

Zhou

2021

IJMS

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“…66 These cells were cultured in DMEM/F-12 supplemented with 20% v/v fetal bovine serum (FBS) (growth media) according to published methods. 67 At 60−70% confluency, cells were replaced with fresh growth media or fresh growth media containing 0.1 μg/mL LPS (lipopolysaccharide from Escherichia coli O111:B4, Sigma). After 24 h, media was removed and cells were incubated with growth media containing vehicle control, 100 nM Cy5−HsTX1[R14A] or 100 nM Cy5−HsTX1-[R14A,Y21A,K23A] for 30 min at 37 °C in 95%/5% O 2 /CO 2 .…”

Section: ■ Discussionmentioning

confidence: 99%

“…BV-2 cells (P31), initially developed in Blasi’s research group, were generously provided by Professor Linda Van Eldik (University of Kentucky, KY) . These cells were cultured in DMEM/F-12 supplemented with 20% v/v fetal bovine serum (FBS) (growth media) according to published methods . At 60–70% confluency, cells were replaced with fresh growth media or fresh growth media containing 0.1 μg/mL LPS (lipopolysaccharide from Escherichia coli O111:B4, Sigma).…”

Section: Methodsmentioning

confidence: 99%

A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel K_V1.3

et al. 2022

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Upregulation of the voltage-gated potassium channel K V 1.3 is implicated in a range of autoimmune and neuroinflammatory diseases, including rheumatoid arthritis, psoriasis, multiple sclerosis, and type I diabetes. Understanding the expression, localization, and trafficking of K V 1.3 in normal and disease states is key to developing targeted immunomodulatory therapies. HsTX1[R14A], an analogue of a 34-residue peptide toxin from the scorpion Heterometrus spinifer, binds K V 1.3 with high affinity (IC 50 of 45 pM) and selectivity (2000-fold for K V 1.3 over K V 1.1). We have synthesized a fluorescent analogue of HsTX1[R14A] by N-terminal conjugation of a Cy5 tag. Electrophysiology assays show that Cy5−HsTX1[R14A] retains activity against K V 1.3 (IC 50 ∼ 0.9 nM) and selectivity over a range of other potassium channels (K.1 and K Ca 3.1), as well as selectivity against heteromeric channels assembled from K V 1.3/K V 1.5 tandem dimers. Live imaging of CHO cells expressing green fluorescent protein-tagged K V 1.3 shows co-localization of Cy5−HsTX1[R14A] and K V 1.3 fluorescence signals at the cell membrane. Moreover, flow cytometry demonstrated that Cy5−HsTX1[R14A] can detect K V 1.3-expressing CHO cells. Stimulation of mouse microglia by lipopolysaccharide, which enhances membrane expression of K V 1.3, was associated with increased staining by Cy5−HsTX1[R14A], demonstrating that it can be used to identify K V 1.3 in disease-relevant models of inflammation. Furthermore, the biodistribution of Cy5−HsTX1[R14A] could be monitored using ex vivo fluorescence imaging of organs in mice dosed subcutaneously with the peptide. These results illustrate the utility of Cy5−HsTX1[R14A] as a tool for visualizing K V 1.3, with broad applicability in fundamental investigations of K V 1.3 biology, and the validation of novel disease indications where K V 1.3 inhibition may be of therapeutic value.

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“…Microglia express various fatty acid transporter proteins, including class B scavenger receptors (SR) such as CD36, ABCD transporters, fatty acid-binding proteins (FABPs) and fatty acid transportation proteins [ 47 – 49 ] that allow uptake of fatty acids. However, the transport of fatty acids from the cytoplasm to mitochondria in microglia seems to have species-specific differences.…”

Section: Dynamics Of Microglial Metabolism and Its Interaction With M...mentioning

confidence: 99%

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics

Lepiarz-Raba,

Gbadamosi,

Florea

et al. 2023

Transl Neurodegener

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Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer’s disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.

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Profiling the expression of fatty acid-binding proteins and fatty acid transporters in mouse microglia and assessing their role in docosahexaenoic acid-d5 uptake

Cited by 6 publications

References 27 publications

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel K_V1.3

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics

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Profiling the expression of fatty acid-binding proteins and fatty acid transporters in mouse microglia and assessing their role in docosahexaenoic acid-d5 uptake

Cited by 6 publications

References 27 publications

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids

A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel KV1.3

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics

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Product

Resources

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A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel K_V1.3