Glucose transporter 1 is important for the glycolytic metabolism of human endometrial stromal cells in hypoxic environment

Abstract Background Solute carrier family 2 member 1 (SLC2A1; previously known as glucose transporter 1), is the most abundant glucose transporter in human endometrium and is up-regulated during decidualization, whereas high insulin may have a negative impact on this process. The present study aimed to investigate the effect of insulin on the expression of SLC2A1 and glucose uptake in decidualizing human endometrial stromal cells. Methods We induced in vitro decidualization of endometrial stromal cells obtained from regularly menstruating healthy non-obese women. The cells were treated with increasing concentrations of insulin, and the involvement of the transcription factor forkhead box O1 (FOXO1) was evaluated using a FOXO1 inhibitor. SLC2A1 mRNA levels were measured by Real-Time PCR and protein levels were evaluated by immunocytochemistry. Glucose uptake was estimated by an assay quantifying the cellular uptake of radioactive glucose. One-way ANOVA, Dunnett’s multiple comparisons test and paired t-test were used to determine the statistical significance of the results. Results We found that insulin dose-dependently decreased SLC2A1 mRNA levels and decreased protein levels of SLC2A1 in decidualizing human endometrial stromal cells. Transcriptional inactivation of FOXO1 seems to explain at least partly the down-regulation of SLC2A1 by insulin. Glucose uptake increased upon decidualization, whereas insulin treatment resulted in a slight inhibition of the glucose uptake, although not significant for all insulin concentrations. Conclusions These results indicate an impairment of decidualization by high concentrations of insulin. Future studies will determine the clinical significance of our results for endometrial function and decidualization in women with insulin resistance and hyperinsulinemia.

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Dehydroepiandrosterone Inhibits Glucose Flux Through the Pentose Phosphate Pathway in Human and Mouse Endometrial Stromal Cells, Preventing Decidualization and Implantation

Molecular Endocrinology ◽

10.1210/me.2011-0026 ◽

2011 ◽

Vol 25 (8) ◽

pp. 1444-1455 ◽

Cited By ~ 44

Author(s):

Antonina I. Frolova ◽

Kathleen O'Neill ◽

Kelle H. Moley

Keyword(s):

Stromal Cells ◽

Pentose Phosphate Pathway ◽

Glucose Transporter ◽

Polycystic Ovary ◽

Pentose Phosphate ◽

Reproductive Age ◽

Endometrial Stromal Cells ◽

Glucose Transporter 1 ◽

Decidual Cells

Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss.

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Adiponectin regulates glycogen metabolism at the human fetal–maternal interface

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0013 ◽

2018 ◽

Vol 61 (3) ◽

pp. 139-152 ◽

Cited By ~ 3

Author(s):

Fabien Duval ◽

Esther Dos Santos ◽

Benoît Maury ◽

Valérie Serazin ◽

Khadija Fathallah ◽

...

Keyword(s):

Molecular Mechanisms ◽

Glucose Transporter ◽

Glycogen Synthesis ◽

Critical Role ◽

Glycogen Metabolism ◽

First Trimester ◽

Endometrial Stromal Cells ◽

Glucose Transporter 1 ◽

Glycogen Accumulation ◽

First Trimester Of Pregnancy

Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal–maternal interface have not yet been characterized. Among the various factors acting at the fetal–maternal interface, we focused on adiponectin – an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal–maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta.

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Stromal Expression of Hypoxia Regulated Proteins Is an Adverse Prognostic Factor in Colorectal Carcinomas

Analytical Cellular Pathology ◽

10.1155/2007/945802 ◽

2007 ◽

Vol 29 (3) ◽

pp. 229-240

Author(s):

Arjen H. G. Cleven ◽

Manon van Engeland ◽

Bradly G. Wouters ◽

Adriaan P. de Bruïne

Keyword(s):

Prognostic Factor ◽

Tumor Cells ◽

Stromal Cells ◽

Glucose Transporter ◽

Tumor Biology ◽

Tumor Hypoxia ◽

Epithelial Tumor ◽

Glucose Transporter 1 ◽

Colorectal Adenocarcinomas ◽

Hypoxia Markers

Background: Hypoxia modifies the phenotype of tumors in a way that promotes tumor aggressiveness and resistance towards chemotherapy and radiotherapy. However, the expression and influence of hypoxia-regulated proteins on tumor biology are not well characterized in colorectal tumors. We studied the role of protein expression of hypoxia-inducible factor (HIF)-1α, HIF-2α, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1) in patients with colorectal adenocarcinomas. Methods: Expression of HIF-1α, HIF-2α, CA9 and GLUT1 was quantified by immunohistochemistry in 133 colorectal adenocarcinomas. The expression of hypoxia markers was correlated with clinicopathological variables and overall patient survival. Results: Expression of these hypoxia markers was detected in the epithelial compartment of the tumor cells as well as in tumor-associated stromal cells. Although tumor cells frequently showed expression of one or more of the investigated hypoxia markers, no correlation among these markers or with clinical response was found. However, within the tumor stroma, positive correlations between the hypoxia markers HIF-2α, CA9 and GLUT1 were observed. Furthermore expression of HIF-2α and CA9 in tumor-associated stroma were both associated with a significantly reduced overall survival. In the Cox proportional hazard model, stromal HIF-2α expression was an independent prognostic factor for survival. Conclusion: These observations show, that expression of hypoxia regulated proteins in tumor-associated stromal cells, as opposed to their expression in epithelial tumor cells, is associated with poor outcome in colorectal cancer. This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis.

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Quantitative Analysis of Glucose Transporter mRNAs in Endometrial Stromal Cells Reveals Critical Role of GLUT1 in Uterine Receptivity

Endocrinology ◽

10.1210/en.2010-1266 ◽

2011 ◽

Vol 152 (5) ◽

pp. 2123-2128 ◽

Cited By ~ 50

Author(s):

Antonina I. Frolova ◽

Kelle H. Moley

Keyword(s):

Stromal Cells ◽

Glucose Transporter ◽

Critical Role ◽

Early Embryo ◽

Absolute Amount ◽

Uterine Receptivity ◽

Endometrial Stromal Cells ◽

Decidual Cells ◽

Before And After ◽

Glut1 Mrna

Recurrent miscarriages affect about 1–2% of couples trying to conceive; however, mechanisms leading to this complication are largely unknown. Most studies focus on the early embryo, but proper development and implantation of the blastocyst are also dependent on optimal endometrial progression into a receptive state. One of the key steps in the uterine preparation for embryo receptivity, known as decidualization, is the differentiation of endometrial stromal cells (ESCs) into decidual cells. During this transition, the ESCs undergo a drastic change in glucose metabolism. The efficiency of glucose uptake is determined by a family of facilitative glucose transporters (GLUTs), and many have been identified in the stroma. The primary focus of this work was to quantify the absolute amount of GLUT mRNAs in this cell type before and after decidualization. We used primary ESCs isolated from murine and human uteri. We developed and validated cDNA-based calibration curves for each GLUT and used these primers to arrive at absolute mRNA copy numbers. Here, we report all the GLUT mRNAs that are present in the ESCs and their abundance under both conditions, control and decidualized. GLUT1 mRNA is the most abundant and critical transporter in ESCs of both species, because knocking down this GLUT with sort hairpin RNA leads to dramatically reduced decidualization. These findings suggest that GLUT1 mRNA expression is essential for decidualization and we are the first to determine a possible mechanism to explain how maternal conditions of abnormal glucose utilization may impair implantation at the level of the ESCs.

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Glucose and Lactate Transport in Pancreatic Cancer: Glycolytic Metabolism Revisited

Journal of Oncology ◽

10.1155/2018/6214838 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Miles E. Cameron ◽

Anastasiya Yakovenko ◽

Jose G. Trevino

Keyword(s):

Pancreatic Cancer ◽

Lactic Acid ◽

Glucose Transporter ◽

Cell Metabolism ◽

Tumor Formation ◽

Membrane Transporters ◽

Ductal Adenocarcinoma ◽

Glycolytic Metabolism ◽

Glucose Transporter 1 ◽

Normal Cellular Function

Membrane transporters fulfill essential roles in maintaining normal cellular function in health. In cancer, transporters likewise facilitate the aberrant characteristics typical of proliferating tumor cells. Pancreatic ductal adenocarcinoma is remarkable in its aggressiveness, and its metabolism is supported by a variety of membrane transporters. Glucose transporter 1 is upregulated in pancreatic cancer, enables rapid cellular uptake of glucose, and contributes to the invasiveness and metastatic ability of the disease. Likewise, the machinery of glycolysis, enzymes such as pyruvate kinase type M2 and hexokinase 2, is particularly active and ultimately leads to both lactate and tumor formation. Lactic acid channels and transporters include monocarboxylate transporters 1 and 4, connexin43, and CD147. In conjunction with glucose transporters and glycolytic metabolism, lactic acid transport helps perpetuate tumor cell metabolism and contributes to the formation of the unique tumor microenvironment in pancreatic cancer. These transporters may serve as potential therapeutic targets.

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Facilitative Glucose Transporter Type 1 Is Differentially Regulated by Progesterone and Estrogen in Murine and Human Endometrial Stromal Cells

Endocrinology ◽

10.1210/en.2008-1081 ◽

2008 ◽

Vol 150 (3) ◽

pp. 1512-1520 ◽

Cited By ~ 63

Author(s):

Antonina Frolova ◽

Lauren Flessner ◽

Maggie Chi ◽

Sung Tae Kim ◽

Nastaran Foyouzi-Yousefi ◽

...

Keyword(s):

Glucose Uptake ◽

Stromal Cells ◽

Glucose Transporter ◽

Glucose Utilization ◽

Embryo Implantation ◽

Endometrial Stromal Cells ◽

Major Player ◽

Glut1 Expression ◽

Facilitative Glucose Transporter

Embryo implantation is a highly synchronized event between an activated blastocyst and a receptive endometrium. The success of this process relies on the dynamic interplay of estrogen (E2) and progesterone (P4), however, the details of this interaction are not entirely clear. Recent data implicate E2 and P4 in the regulation of glucose utilization by affecting facilitative glucose transporter (GLUT) expression. In this study we examine GLUT1 expression in murine and human endometrial stromal cells (ESCs) using a primary culture system. We show that expression of GLUT1 is increased during ESC decidualization in vitro. P4 up-regulates, whereas E2 down-regulates, GLUT1 expression. In addition, P4 increases and E2 decreases glucose uptake in ESCs, suggesting that GLUT1 may be a major player in glucose utilization in these cells. Moreover, GLUT1 expression is increased in human ESCs when decidualized in vitro with P4 and dibutyryl cAMP, suggesting a similar role for P4 in human endometrium. In conclusion, an imbalance between P4 and E2 seen in patients with polycystic ovary syndrome, luteal phase defect, and recurrent pregnancy loss may have a critical impact on glucose utilization in the endometrial stroma, and, thus, may be responsible for endometrial dysfunction and failure of embryo implantation in these patient populations. GLUT1 expression increases during decidualization of endometrial stromal cells in vitro. Progesterone upregulates and estrogen downregulates GLUT1 expression and glucose uptake in these cells.

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Dysregulated GLUT1 May Be Involved in the Pathogenesis of Preeclampsia by Impairing Decidualization

10.21203/rs.3.rs-842160/v1 ◽

2021 ◽

Author(s):

Man Yang ◽

Hua Li ◽

Miaomiao Rong ◽

Hongya Zhang ◽

Linlin Hou ◽

...

Keyword(s):

Glucose Uptake ◽

Glucose Transporter ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Target Prediction ◽

Mrna Levels ◽

Endometrial Stromal Cells ◽

Glucose Transporter 1

Abstract Background: Preeclampsia (PE), a hypertensive complication in pregnancy, is a major contributor to maternal and fetal morbidity and mortality. Thus far, the molecular mechanism underlying PE has not been investigated thoroughly. Glucose transporter 1 (GLUT1) is a central rate-limiting pump for glucose uptake and subsequent utilization. Our previous RNA-seq results demonstrated it was significantly downregulated in deciduas from severe PE patients. Therefore, we aimed to explore the role of GLUT1 in the occurrence of PE.Methods: In this study, GLUT1 levels were evaluated by quantitative PCR, Western blotting and immunohistochemical staining in severe preeclamptic deciduas. The levels of GLUT1 during decidualization were also studied in human endometrial stromal cells (hESCs). Moreover, the role of GLUT1 during decidualization was studied by GLUT1-siRNA treatment. Furthermore, we explored the regulatory role of miRNA in GLUT1 expression.Results: The expression of GLUT1 was significantly downregulated in the deciduas from severe PE patients. Additionally, the level of GLUT1 was substantially induced in hESCs during in vitro decidualization. Moreover, GLUT1 knockdown significantly reduced the mRNA levels of decidualization markers (IGFBP1 and PRL) and aerobic glycolysis-related genes (LDHA and MCT4), and decreased glucose uptake and lactate production. Furthermore, the levels of apoptotic genes P53, P21 and BAX increased whereas the levels of BCL2 decreased after GLUT1 knockdown. Target prediction results and luciferase analysis showed GLUT1 is one of the targets of miR-140-5p, which is partly responsible for the impaired GLUT1 level. Conclusion: These results demonstrate that GLUT1 exerts pivotal role in human decidualization by participating in glycolysis, and its deficiency may trigger aberrant glycolysis and thus leads to destructive decidualization, which may be a pathogenetic mechanism of PE. These data suggest GLUT1 might be a promising target for PE therapy.

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