scholarly journals Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1

2007 ◽  
Vol 293 (1) ◽  
pp. C477-C485 ◽  
Author(s):  
Marc U. Baumann ◽  
Stacy Zamudio ◽  
Nicholas P. Illsley
Keyword(s):  
Glucose Transport ◽  
Oxygen Tension ◽  
Glucose Transporter ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Trophoblast Cell ◽  
Low Oxygen ◽  
Bewo Cells ◽  
Glut1 Expression ◽  
Choriocarcinoma Cells

Placental hypoxia has been implicated in pregnancy pathologies, including fetal growth restriction and preeclampsia; however, the mechanism by which the trophoblast cell responds to hypoxia has not been adequately explored. Glucose transport, a process crucial to fetoplacental growth, is upregulated by hypoxia in a number of cell types. We investigated the effects of hypoxia on the regulation of trophoblast glucose transporter (GLUT) expression and activity in BeWo choriocarcinoma cells, a trophoblast cell model, and human placental villous tissue explants. GLUT1 expression in BeWo cells was upregulated by the hypoxia-inducing chemical agents desferroxamine and cobalt chloride. Reductions in oxygen tension resulted in dose-dependent increases in GLUT1 and GLUT3 expression. Exposure of cells to hypoxic conditions also resulted in an increase in transepithelial glucose transport. A role for hypoxia-inducible factor (HIF)-1 was suggested by the increase in HIF-1α as a result of hypoxia and by the increase in GLUT1 expression following treatment of BeWo with MG-132, a proteasomal inhibitor that increases HIF-1 levels. The function of HIF-1 was confirmed in experiments where the hypoxic upregulation of GLUT1 and GLUT3 was inhibited by antisense HIF-1α. In contrast to BeWo cells, hypoxia produced minimal increases in GLUT1 expression in explants; however, treatment with MG-132 did upregulate syncytial basal membrane GLUT1. Our results show that GLUTs are upregulated by hypoxia via a HIF-1-mediated pathway in trophoblast cells and suggest that the GLUT response to hypoxia in vivo will be determined not only by low oxygen tension but also by other factors that modulate HIF-1 levels.

scholarly journals Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells

2004 ◽  
Vol 183 (1) ◽  
pp. 145-154 ◽  
Author(s):  
Masami Hayashi ◽  
Masahiro Sakata ◽  
Takashi Takeda ◽  
Toshiya Yamamoto ◽  
Yoko Okamoto ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Level ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Hypoxic Conditions ◽  
Glut1 Expression ◽  
Oxygen Conditions ◽  
Responsive Element

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose in the placenta. During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development, and GLUT1 expression is enhanced in response to oxygen deficiency in the placenta. Hypoxia-inducible factor-1 (HIF-1)α is involved in the induction of GLUT1 expression in other cells. The present study was designed to test whether HIF-1α is involved in hypoxia-induced activation of GLUT1 expression using trophoblast-derived human BeWo and rat Rcho-1 cells as models. GLUT1 mRNA and protein expression were elevated under 5% O2 or in the presense of cobalt chloride, which has been shown to mimic hypoxia. Using rat GLUT1 (rGLUT1) promoter–luciferase constructs, we showed that this up-regulation was mediated at the transcriptional level. Deletion mutant analysis of the rGLUT1 promoter indicated that a 184 bp hypoxia-responsive element (HRE) of the promoter was essential to increase GLUT1 reporter gene expression in response to low-oxygen conditions. BeWo and Rcho-1 cells cultured under 5% O2 or with CoCl2 showed increased expression of HIF-1α protein compared with those cultured under 20% O2. To test whether this factor is directly involved in hypoxia-induced GLUT1 promoter activation, BeWo and Rcho-1 cells were transiently transfected with an HIF-1α expression vector. Exogeneous HIF-1α markedly increased the GLUT1 promoter activity from constructs containing the HRE site, while the GLUT1 promoter constructs lacking the HRE site were not activated by exogenous HIF-1α These data demonstrate that GLUT1 is up-regulated under 5% O2 or in the presence of CoCl2 in the placental cell lines through HIF-1α interaction with a consensus HRE site of the GLUT1 promoter.

HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

2013 ◽  
Vol 83 (3) ◽  
pp. 188-197 ◽  
Author(s):  
Rebecca L. Sweet ◽  
Jason A. Zastre
Keyword(s):  
Gene Expression ◽  
Thiamine Deficiency ◽  
Glucose Transporter ◽  
Neuroblastoma Cell ◽  
Hypoxia Inducible Factor ◽  
Clinical Manifestations ◽  
Vitamin B1 ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

scholarly journals Integrin α6 upregulation in nucleus pulposus cell under high oxygen tension attenuates intervertebral disc degeneration

2021 ◽  
Author(s):  
Zeng Xu ◽  
Jiancheng Zheng ◽  
Ying Zhang ◽  
Huiqiao Wu ◽  
Bin Sun ◽  
...  
Keyword(s):  
Oxygen Tension ◽  
Protective Factor ◽  
Cell Function ◽  
Hypoxia Inducible Factor ◽  
Nucleus Pulposus Cell ◽  
Intervertebral Disk ◽  
High Oxygen ◽  
Low Oxygen ◽  
Induced Apoptosis

AbstractThe destruction of low oxygen microenvironment played critical roles in the pathogenesis of intervertebral disk degeneration (IVDD). In this study, high oxygen tension (HOT) treatment upregulated integrin α6(ITG α6) expression, which could be alleviated by blocking PI3K/AKT signaling pathway. And the levels of ITG α6 expression were increased in the NP tissue from IVDD patients and IVDD rat model with mild degeneration, which were reduced as degeneration degree increases. Further studies found that ITG α6 could protect NP cells against HOT-induced apoptosis and oxidative stress, and protect NP cells from HOT-inhibited ECM proteins synthesis. ITG α6 upregulation by HOT contributed to maintain a NP tissue homeostasis through the interaction with hypoxia inducible factor-1α (HIF-1α). Furthermore, silencing of ITG α6 in vivo could obviously accelerate puncture-induced IVDD. Taken together, ITG α6 upregulation by HOT in NP cells might be a protective factor in IVDD as well as restore NP cell function.

scholarly journals Plumbagin attenuates high glucose-induced trophoblast cell apoptosis and insulin resistance via activating AKT/mTOR pathway

2021 ◽  
Vol 13 (3) ◽  
pp. 102-108
Author(s):  
Yilin Zhang ◽  
Guantai Ni ◽  
Hongying Yang
Keyword(s):  
Insulin Resistance ◽  
Cell Viability ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Glucose Transporter ◽  
Cell Model ◽  
Trophoblast Cell ◽  
Mtor Pathway ◽  
Potential Strategy ◽  
Glucose Transporter Type 4

Plumbagin, a bioactive phytoconstituent, is isolated from the root of Plumbago zeylanica L. Plumbagin pos-sesses antidiabetic effect to mediate glucose homeostasis, wound healing and diabetic nephropathy. However, the involvement of plumbagin in gestational diabetes mellitus (GDM) has not been reported yet. Trophoblast cell line (HTR8/SVneo) was incubated with high glucose to establish cell model of GDM. Cell viability and proliferation were detected by MTT and EdU staining. Flow cytometry was used to investigate cell apoptosis. Cell viability of HTR8/SVneo was reduced by high glucose or incubation of plumbagin. Plumbagin restored reduced cell viability and proliferation of HTR8/SVneo induced by high glucose. Plumbagin attenuated high glucose-induced cell apoptosis in HTR8/SVneo cells through upregulation of Bcl-2 and down-regulation of Bax, cleaved caspase-3 and cleaved caspase-9. Protein expression of glucose transporter type 4 (GLUT-4), insulin receptor (INSR)-B and INSR substrate (IRS1) was decreased in high glucose-induced HTR8/SVneo but increased by plumbagin. The suppressive effects of high glucose on phosphorylation of AKT and mTOR in HTR8/SVneo were reversed by plumbagin. Plumbagin improved high glucose-induced cell apoptosis and insulin resistance of HTR8/SVneo through activation of AKT/mTOR pathway, suggesting that plumbagin might be used as a potential strategy for the prevention of GDM.

scholarly journals Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors

2012 ◽  
Vol 303 (10) ◽  
pp. G1164-G1173 ◽  
Author(s):  
Martin Haugen ◽  
Rikard Dammen ◽  
Bernhard Svejda ◽  
Bjorn I. Gustafsson ◽  
Roswitha Pfragner ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Mechanical Stretch ◽  
Renilla Luciferase ◽  
Low Oxygen ◽  
Differential Signal ◽  
Oxygen Levels ◽  
Ec Cells

The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O2. Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O2would reduce 5-HT production and secretion. Isolated normal EC cells as well as the well-characterized EC cell model KRJ-I were used to examine HIF signaling (luciferase-assays), hypoxia transcriptional response element (HRE)-mediated transcription (PCR), signaling pathways (Western blot), and 5-HT release (ELISA) during exposure to different oxygen levels. Normal EC cells and KRJ-I cells express HIF-1α, and transient transfection with Renilla luciferase under HRE control identified a hypoxia-mediated pathway in these cells. PCR confirmed activation of HIF-downstream targets, GLUT1, IGF2, and VEGF under reduced O2levels (0.5%). Reducing O2also elevated 5-HT secretion (2–3.2-fold) as well as protein levels of HIF-1α (1.7–3-fold). Increasing O2to 100% inhibited HRE-mediated signaling, transcription, reduced 5-HT secretion, and significantly lowered HIF-1α levels (∼75% of control). NF-κB signaling was also elevated during hypoxia (1.2–1.6-fold), but no significant changes were noted in PKA/cAMP. We concluded that gut EC cells are oxygen responsive, and alterations in O2levels differentially activate HIF-1α and tryptophan hydroxylase 1, as well as NF-κB signaling. This results in alterations in 5-HT production and secretion and identifies that the chemomechanosensory role of EC cells extends to oxygen sensing.

scholarly journals Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

2015 ◽  
Vol 35 (3) ◽  
pp. 841-857 ◽  
Author(s):  
Sophie Portron ◽  
Vincent Hivernaud ◽  
Christophe Merceron ◽  
Julie Lesoeur ◽  
Martial Masson ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Oxygen Tension ◽  
Stromal Cells ◽  
Chondrogenic Differentiation ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Cartilage Tissue Engineering ◽  
Cartilage Tissue ◽  
Low Oxygen ◽  
Dna Binding Assay

Background/Aims: Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O2) or hypoxic (5%O2) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.

Stimulation of Glucose Transport by Hypoxia: Signals and Mechanisms

Physiology ◽  
1999 ◽  
Vol 14 (3) ◽  
pp. 105-110 ◽  
Author(s):  
Alireza Behrooz ◽  
Faramarz Ismail-Beigi
Keyword(s):  
Oxidative Phosphorylation ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Glut 1 ◽  
Hypoxia Inducible Factor 1 ◽  
Glut 4 ◽  
Per Se ◽  
Stimulation Of

Glucose transport is acutely stimulated by hypoxia through enhanced GLUT-1 and GLUT-4 glucose transporter function. GLUT-1 expression is also stimulated by hypoxia or azide. Moreover, hypoxia per se, acting through hypoxia-inducible factor 1, enhances GLUT-1 transcription. GLUT-1 is the first gene whose transcription is dually stimulated in response to hypoxia and inhibition of oxidative phosphorylation.

scholarly journals Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells

2004 ◽  
Vol 182 (3) ◽  
pp. 467-478 ◽  
Author(s):  
RA Medina ◽  
AM Meneses ◽  
JC Vera ◽  
C Guzman ◽  
F Nualart ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Energy Requirement ◽  
Cancer Cell Line ◽  
Glut4 Expression ◽  
Glut1 Expression ◽  
Glut Expression ◽  
Hormonal Treatments

Estrogen replacement therapy and other unopposed estrogen treatments increase the incidence of endometrial abnormalities, including cancer. However, this effect is counteracted by the co-administration of progesterone. In the endometrium, glucose transporter (GLUT) expression and glucose transport are known to fluctuate throughout the menstrual cycle. Here, we determined the effect of estrogen and progesterone on the expression of GLUT1-4 and on the transport of deoxyglucose in Ishikawa endometrial cancer cells. Cells were incubated with estrogen, progesterone or combined estrogen and progesterone for 24 h and the effect on the expression of GLUT1-4 and on deoxyglucose transport was determined. We show that GLUT1 expression is upregulated by estrogen and progesterone individually, but that combined estrogen and progesterone treatment reverses this increase. Hormonal treatments do not affect GLUT2, GLUT3 or GLUT4 expression. Transport studies demonstrate that estrogen increases deoxyglucose transport at Michaelis-Menten constants (Kms) corresponding to GLUT1/4, an effect which disappears when progesterone is added concomitantly. These data demonstrate that different hormonal treatments differentially regulate GLUT expression and glucose transport in this endometrial cancer cell line. This regulation mirrors the role played by estrogen and progesterone on the incidence of cancer in this tissue and suggests that GLUT1 may be utilized by endometrial cancer cells to fuel their demand for increased energy requirement.

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