Influence of genetic copy number variants of the human GLUT3 glucose transporter gene SLC2A3 on protein expression, glycolysis and rheumatoid arthritis risk: A genetic replication study

Simpfendorfer, Kim R.; Li, Wentian; Shih, Andrew; Wen, Hongxiu; Kothari, Harini P.; Einsidler, Edward A.; Wüster, Arthur; Hunkapiller, Julie; Behrens, Timothy W.; Graham, Robert; Townsend, Michael J.; Behar, Doron M.; Hu, Rui; Greenspan, Elliott; Gregersen, Peter K.

doi:10.1016/j.ymgmr.2019.100470

Cited by 4 publications

(5 citation statements)

References 22 publications

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“…Whether GLUT3 protein expression reflects this increased transcription in duplication carriers remains controversial. To date, only a single study by Vittori et al (2014) found increased protein expression in cell lines from duplication carriers, whereas we and others did not observe such an effect in similar experimental settings (Merker et al, 2017; Simpfendorfer et al, 2019). Furthermore, the duplication variant did not affect glucose uptake levels in lymphoblastoid cells under basal conditions (Merker et al, 2017).…”

Section: The Glucose Transporter Glut3contrasting

confidence: 59%

“…These data suggest that SLC2A3 may provide a protective effect against RA. However, in a higher‐powered independent replication study, this association was not observed (Simpfendorfer et al, 2019). Although initial results may have been a false positive, it is also possible that there is a population‐specific effect of SLC2A3 CNVs on different disease phenotypes (Merker et al, 2017).…”

Section: Slc2a3 Copy Number Variation and Associated Clinical Phenotypesmentioning

confidence: 97%

“…There are not many studies which have investigated whether SLC2A3 CNVs can alter downstream metabolic pathways, and systematic analyses determining whether compensatory/transregulatory expression changes in non‐GLUT genes may occur are lacking. An initial study has reported reduced glycolytic activity in the immune cells of deletion carriers (Simpfendorfer et al, 2019), which could potentially lead to cellular growth restriction. Synaptic outgrowth has also been observed reduced in murine neurons with SLC2A3 knockdown in early postnatal development, supporting the role of GLUT3 as an important factor in neuronal maturation (Segarra‐Mondejar et al, 2018).…”

Section: The Glucose Transporter Glut3mentioning

confidence: 99%

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Cellular effects and clinical implications of SLC2A3 copy number variation

Ziegler

Álmos

McNeill

et al. 2020

Journal Cellular Physiology

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SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non‐allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.

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Section: The Glucose Transporter Glut3contrasting

confidence: 59%

Section: Slc2a3 Copy Number Variation and Associated Clinical Phenotypesmentioning

confidence: 97%

Section: The Glucose Transporter Glut3mentioning

confidence: 99%

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Cellular effects and clinical implications of SLC2A3 copy number variation

Ziegler

Álmos

McNeill

et al. 2020

Journal Cellular Physiology

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“… 50 Interestingly, deletion of SLC2A3 the gene encoding GLUT3 can prevent RA-related joint injuries, indicating that as a glycolysis-related protein GLUT3 is a potential therapeutic target for RA. 51 It is apparent that up-regulation of either HKs or GLUT would facilitate glycolysis. Indeed, HK2 and GLUT are highly expressed in RA synovium, which is believed to be a driving force for the enhanced migration and invasion ability of FLSs.…”

Section: Involvement Of Energy Metabolism Alteration In Ramentioning

confidence: 99%

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication

Luo¹,

Wu²,

Yin³

et al. 2023

JIR

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Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.

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“…There are only a few reports on GLUT1, GLUT3 and GLUT4 in RA. Heterozygous deletion of GLUT3 correlates directly with expression levels of GLUT3 and influences glycolysis rates in the human immune system ( 46 ), but the frequency of the GLUT3 copy number variant is not different among RA, multiple sclerosis and heathy control, providing no evidence for RA protection in deletion of GLUT3 ( 46 ), the study of which demonstrated GLUT3 is not necessary for glucose transfer in patients with RA. However, another study showed the mutual activation between CD4 + T cells and FLS, which resulted in increased proliferation and expression of glucose transporters GLUT1 and GLUT3 in FLS ( 47 ).…”

Section: Glucose Metabolism As An Arthritogenic Risk Factormentioning

confidence: 99%

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

Qiu

Goodman

et al. 2021

Front. Immunol.

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Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

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Influence of genetic copy number variants of the human GLUT3 glucose transporter gene SLC2A3 on protein expression, glycolysis and rheumatoid arthritis risk: A genetic replication study

Cited by 4 publications

References 22 publications

Cellular effects and clinical implications of SLC2A3 copy number variation

Cellular effects and clinical implications of SLC2A3 copy number variation

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

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