Glut1 and Glut3 as Potential Prognostic Markers for Oral Squamous Cell Carcinoma

We associated clinical-pathological features of 142 OSCC with the expression pattern of GLUT1 and GLUT3 in order to estimate their prognostic value. Methods: Clinical-pathological features and overall survival data of 142 patients with Oral Squamous Cell Carcinoma (OSCC) were retrospectively reviewed from A. C. Camargo hospital records. A tissue microarray (TMA) was built for the immunohistochemical (IHC) analysis of GLUT 1 and GLUT 3. IHC results were evaluated according to the staining pattern and number of positive cells. Results: GLUT 1 was over expressed in 50.3% of OSSC cases showing membrane staining pattern. However, nuclear expression was observed in 49.7% of the analyzed cases. GLUT 3 over expression was detected in 21.1% of OSCC cases. The pattern of GLUT 1 expression showed significant association with alcohol consumption (p = 0.004). Positive cell membrane GLUT 3 protein expression was associated with advanced clinic-staging of tumours (p = 0.005) as well as with vascular embolization (p = 0.005). Positive expression of GLUT 3 was associated with unfavorable free-disease survival (p = 0.021). Conclusion: GLUT1 and GLUT3 protein expression evaluated by immunohistochemistry are, significantly, indicators of poor prognosis outcome in oral squamous cell carcinoma, probably due to the enhanced glycolytic metabolism of more aggressive neoplastic cells.

GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer.

BACKGROUND: Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. Here we show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT. RESULTS: Using a panel of human non-small cell lung cancer (NSCLC) cell lines, we demonstrate that GLUT3 is strongly expressed in mesenchymal, but not epithelial cells, a finding corroborated in hepatoma cells. Furthermore, we identify that ZEB1 binds to the GLUT3 gene to activate transcription. Importantly, inhibiting GLUT3 expression reduces glucose import and the proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. Using a large microarray data collection of human NSCLCs, we determine that GLUT3 expression correlates with EMT markers and is prognostic of poor overall survival. CONCLUSIONS: Altogether, our results reveal that GLUT3 is a transcriptional target of ZEB1 and that this glucose transporter plays an important role in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Moreover, these findings emphasize the development of GLUT3 inhibitory drugs as a targeted therapy for the treatment of patients with poorly differentiated tumors.

Triiodothyronine Acutely Stimulates Glucose Transport into L6 Muscle Cells Without Increasing Surface GLUT4, GLUT1, or GLUT3

Background: Thyroid hormones (THs) act genomically to stimulate glucose transport by elevating glucose transporter (Slc2a) expression and glucose utilization by cells. However, nongenomic effects of THs are now emerging. Here, we assess how triiodothyronine (T-3) acutely affects glucose transport and the content of GLUT4, GLUT1, and GLUT3 at the surface of muscle cells, and possible interactions between T-3 and insulin action. Methods: Differentiated L6 myotubes transfected with myc-tagged Slc2a4 (L6-GLUT4myc) or Slc2a1 (L6-GLUT1myc) and wild-type L6 myotubes were studied in the following conditions: control, hypothyroid (Tx), Tx plus T3, Tx plus insulin, and Tx plus insulin and T-3. Results: Glucose uptake and GLUT4 content at the cell surface decreased in the Tx group relative to controls. T-3 treatment for 30 minutes increased glucose transport into L6-GLUT4myc cells without altering surface GLUT4 content, which increased only thereafter. The total amount of GLUT4 protein remained unchanged among the groups studied. The surface GLUT1 content of L6-GLUT1myc cells also remained unaltered after T-3 treatment; however, in these cells glucose transport was not stimulated by T-3. In wild-type L6 cells, although T-3 treatment increased the total amount of GLUT3, it did not change the surface GLUT3 content. Moreover, within 30 minutes, T-3 stimulation of glucose uptake was additive to that of insulin in L6-GLUT4myc cells. As expected, insulin elevated surface GLUT4 content and glucose uptake. However, interestingly, surface GLUT4 content remained unchanged or even dropped with T-3 plus insulin. Conclusions: These data reveal that T-3 rapidly increases glucose uptake in L6-GLUT4myc cells, which, at least for 30 minutes, did not depend on an increment in GLUT4 at the cell surface yet potentiates insulin action. We propose that this rapid T-3 effect involves activation of GLUT4 transporters at the cell surface, but cannot discount the involvement of an unknown GLUT.

Messenger RNA expression of transporter and ion channel genes in undifferentiated and differentiated Caco-2 cells compared to human intestines.

PURPOSE: The purpose of this work was to study the influence of cell differentiation on the mRNA expression of transporters and channels in Caco-2 cells and to assess Caco-2 cells as a model for carrier-mediated drug transport in the intestines. METHOD: Gene mRNA expression was measured using a custom-designed microarray chip with 750 deoxyoligonucleotide probes (70mers). Each oligomer was printed four times on poly-lysine-coated glass slides. Expression profiles were expressed as ratio values between fluorescence intensities of Cy3 and Cy5 dye-labeled cDNA derived from poly(A) + RNA samples of Caco-2 cells and total RNA of human intestines. RESULTS: Significant differences in the mRNA expression profile of transporters and channels were observed upon differentiation of Caco-2 cells from 5 days to 2 weeks in culture, including changes for MAT8, S-protein, and Nramp2. Comparing Caco-2 cells of different passage number revealed few changes in mRNAs except for GLUT3, which was down-regulated 2.4-fold within 13 passage numbers. Caco-2 cells had a similar expression profile when either cultured in flasks or on filters but differed more strongly from human small and large intestine, regardless of the differentiation state of Caco-2 cells. Expression of several genes highly transcribed in small or large intestines differed fourfold or more in Caco-2 cells. CONCLUSIONS: Although Caco-2 cells have proven a suitable model for studying carrier-mediated transport in human intestines, the expression of specific transporter and ion channel genes may differ substantially.

Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014;62:1125-1141.

Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat.

The lithium-pilocarpine model mimics most features of human temporal lobe epilepsy. Following our prior studies of cerebral metabolic changes, here we explored the expression of transporters for glucose (GLUT1 and GLUT3) and monocarboxylates (MCT1 and MCT2) during and after status epilepticus (SE) induced by lithium-pilocarpine in PN10, PN21, and adult rats. In situ hybridization was used to study the expression of transporter mRNAs during the acute phase (1, 4, 12 and 24h of SE), the latent phase, and the early and late chronic phases. During SE, GLUT1 expression was increased throughout the brain between 1 and 12h of SE, more strongly in adult rats; GLUT3 increased only transiently, at 1 and 4h of SE and mainly in PN10 rats; MCT1 was increased at all ages but 5-10-fold more in adult than in immature rats; MCT2 expression increased mainly in adult rats. At all ages, MCT1 and MCT2 up-regulation was limited to the circuit of seizures while GLUT1 and GLUT3 changes were more widespread. During the latent and chronic phases, the expression of nutrient transporters was normal in PN10 rats. In PN21 rats, GLUT1 was up-regulated in all brain regions. In contrast, in adult rats GLUT1 expression was down-regulated in the piriform cortex, hilus and CA1 as a result of extensive neuronal death. The changes in nutrient transporter expression reported here further support previous findings in other experimental models demonstrating rapid transcriptional responses to marked changes in cerebral energetic/glucose demand.

Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain--an immunohistochemical study.

The aim of this work was to study the distribution and cellular localization of GLUT2 in the rat brain by light and electron microscopic immunohistochemistry, whereas our ultrastructural observations will be reported in a second paper. Confirming previous results, we show that GLUT2-immunoreactive profiles are present throughout the brain, especially in the limbic areas and related nuclei, whereas they appear most concentrated in the ventral and medial regions close to the midline. Using cresyl violet counterstaining and double immunohistochemical staining for glial or neuronal markers (GFAp, CAII and NeuN), we show that two limited populations of oligodendrocytes and astrocytes cell bodies and processes are immunoreactive for GLUT2, whereas a cross-reaction with GLUT1 cannot be ruled out. In addition, we report that the nerve cell bodies clearly immunostained for GLUT2 were scarce (although numerous in the dentate gyrus granular layer in particular), whereas the periphery of numerous nerve cells appeared labeled for this transporter. The latter were clustered in the dorsal endopiriform nucleus and neighboring temporal and perirhinal cortex, in the dorsal amygdaloid region, and in the paraventricular and reuniens thalamic nuclei, whereas they were only a few in the hypothalamus. Moreover, a group of GLUT2-immunoreactive nerve cell bodies was localized in the dorsal medulla oblongata while some large multipolar nerve cell bodies peripherally labeled for GLUT2 were scattered in the caudal ventral reticular formation. This anatomical localization of GLUT2 appears characteristic and different from that reported for the neuronal transporter GLUT3 and GLUT4. Indeed, the possibility that GLUT2 may be localized in the sub-plasmalemnal region of neurones and/or in afferent nerve fibres remains to be confirmed by ultrastructural observations. Because of the neuronal localization of GLUT2, and of its distribution relatively similar to glucokinase, it may be hypothesized that this transporter is, at least partially, involved in cerebral glucose sensing.

Glucose uptake, utilization, and signaling in GLUT2-null islets.

We previously reported that pancreatic islet beta-cells from GLUT2-null mice lost the first phase but preserved the second phase of glucose-stimulated insulin secretion (GSIS). Furthermore, we showed that the remaining secretory activity required glucose uptake and metabolism because it can be blocked by inhibition of oxidative phosphorylation. Here, we extend these previous studies by analyzing, in GLUT2-null islets, glucose transporter isoforms and glucokinase expression and by measuring glucose usage, GSIS, and glucose-stimulated insulin mRNA biosynthesis. We show that in the absence of GLUT2, no compensatory expression of either GLUT1 or GLUT3 is observed and that glucokinase is expressed at normal levels. Glucose usage by isolated islets was increased between 1 and 6 mmol/l glucose but was not further increased between 6 and 20 mmol/l glucose. Parallel GSIS measurements showed that insulin secretion was not stimulated between 2.8 and 6 mmol/l glucose but was increased by >4-fold between 6 and 20 mmol/l glucose. Stimulation by glucose of total protein and insulin biosynthesis was also markedly impaired in the absence of GLUT2. Finally, we re-expressed GLUT2 in GLUT2-null beta-cells using recombinant lentiviruses and demonstrated a restoration of normal GSIS. Together, these data show that in the absence of GLUT2, glucose can still be taken up by beta-cells, albeit at a low rate, and that this transport activity is unlikely to be attributed to GLUT1 or GLUT3. This uptake activity, however, is limiting for normal glucose utilization and signaling to secretion and translation. These data further demonstrate the key role of GLUT2 in murine beta-cells for glucose signaling to insulin secretion and biosynthesis.

Effects of sciatic nerve transection on ultrastructure, NADPH-diaphorase reaction and serotonin-, tyrosine hydroxylase-, c-Fos-, glucose transporter 1- and 3-like immunoreactivities in frog dorsal root ganglion

Frogs have been used as an alternative model to study pain mechanisms. Since we did not find any reports on the effects of sciatic nerve transection (SNT) on the ultrastructure and pattern of metabolic substances in frog dorsal root ganglion (DRG) cells, in the present study, 18 adult male frogs (Rana catesbeiana) were divided into three experimental groups: naive (frogs not subjected to surgical manipulation), sham (frogs in which all surgical procedures to expose the sciatic nerve were used except transection of the nerve), and SNT (frogs in which the sciatic nerve was exposed and transected). After 3 days, the bilateral DRG of the sciatic nerve was collected and used for transmission electron microscopy. Immunohistochemistry was used to detect reactivity for glucose transporter (Glut) types 1 and 3, tyrosine hydroxylase, serotonin and c-Fos, as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase). SNT induced more mitochondria with vacuolation in neurons, satellite glial cells (SGCs) with more cytoplasmic extensions emerging from cell bodies, as well as more ribosomes, rough endoplasmic reticulum, intermediate filaments and mitochondria. c-Fos immunoreactivity was found in neuronal nuclei. More neurons and SGCs surrounded by tyrosine hydroxylase-like immunoreactivity were found. No change occurred in serotonin- and Glut1- and Glut3-like immunoreactivity. NADPH-diaphorase occurred in more neurons and SGCs. No sign of SGC proliferation was observed. Since the changes of frog DRG in response to nerve injury are similar to those of mammals, frogs should be a valid experimental model for the study of the effects of SNT, a condition that still has many unanswered questions.

Investigation of the Expression of Glucose Transporter Proteins in Human Cancer Cells

Cancer cells are known to display increased glucose uptake and consumption. The glucose transporter (GLUT) proteins facilitate glucose uptake, however, their exact role in cancer metabolism remains unclear. The present study examined mRNA and protein expression of GLUT1, GLUT3, GLUT4 and GLUT12 in lung, breast and prostate cancer cells and corresponding noncancerous cells. Additionally, GLUT expression was determined in tumours from mice xenografted with human cancer cells. Differences in the mRNA and protein expression of GLUTs were found between cancerous and corresponding noncancerous cells. These findings demonstrate abundant expression of GLUT1 in cancer and highlight the importance of GLUT3 as it was expressed in several cancer cells and tumours. GLUT expression patterns in vitro were supported by the in vivo findings. The study of GLUT protein expression in cancer is important for understanding cancer metabolism and may lead to identification of biomarkers of cancer progression and development of target therapies.

Muscarinic M1, M3, Nicotinic,GABAA and GABAB Receptor Subtypes Gene Expression in Insulin Induced Hypoglycemic Rat Brain Regions: Functional Regulation through Phospholipase C and CREB Protein

In the present study, a detailed investigation on the alterations of muscarinic M1, M3, α7 nicotinic acetylcholine receptor (α7 nAchR), GABA receptors and its subtypes; GABAAα1 and GABAB in the brain regions of streptozotocin induced diabetic and insulin induced hypoglycemic rats were carried out. Gene expression of acetylcholine esterase (AChE), choline acetyltransferase (ChAT), GAD, GLUT3, Insulin receptor, superoxide dismutase (SOD), Bax protein, Phospholipase C and CREB in hypoglycemic and hyperglycemic rat brain were studied. Muscarinic M1, M3 receptors, AChE, ChAT, GABAAα1, GABAB, GAD, Insulin receptor, SOD, Bax protein and Phospholipase C expression in pancreas was also carried out. The molecular studies on the CNS and PNS damage will elucidate the therapeutic role in the corrective measures of the damage to the brain during hypoglycemia and hyperglycemia.

Neuronal degeneration in streptozotocin induced diabetic rats: Effect of Aegle marmelose and pyridoxine in pancreatic cell proliferation and neuronal Surviva

This thesis Entitled Neuronal degeneration in streptozotocin induced diabetic rats: effect of aegle marmelose and pyridoxine in pancreatic B cell proliferation and neuronal survival. Diabetes mellitus, a chronic metabolic disorder results in neurological dysfunctions and structural changes in the CNS. Antioxidant therapy is a challenging but necessary dimension in the management of diabetes and neurodegenerative changes associated with it. Our results showed regional variation and imbalance in the expression pattern of dopaminergic receptor subtypes in diabetes and its role in imbalanced insulin signaling and glucose regulation. Disrupted dopaminergic signaling and increased hyperglycemic stress in diabetes contributed to the neuronal loss. Neuronal loss in diabetic rats mediated through the expression of pattern of GLUT-3, CREB, IGF-1, Akt-1, NF,B, second messengers- cAMP, cGMP, IP3 and activation of apoptotic factors factors- TNF-a,caspase-8. Disrupted dopaminergic receptor expressions and its signaling in pancreas contributed defective insulin secretion in diabetes. Activation of apoptotic factors- TNF- a,caspase-8 and defective functioning of neuronal survival factors, disrupted second messenger signaling modulated neuronal viability in diabetes. Hyperglycemic stress activated the expression of TNF-a,caspase-8, BAX and differential expression of anti oxidant enzymes- SOD and GPx in liver lead to apoptosis. Treatment of diabetic rats with insulin, Aegle marmelose and pyridoxine significantly reversed the altered dopaminergic neurotransmission, GLUT3, GLUT2, IGF-1 and second messenger signaling. Antihyperglycemic and antioxidant activity of Aegle marmelose and pyridoxine enhanced pancreatic B cell proliferation, increased insulin synthesis and secretion in diabetic rats. Thus our results conclude the neuroprotective and regenerating ability of Aegle marmelose and pyridoxine which in turn has a novel therapeutic role in the management of diabetes.

A practical approach on boar sperm cryodamage. Morphofunctional and immunocytochemical study of cryopreserved boar sperm intended for use in artificial insemination

L'ús d'esperma criopreservada en la inseminació artificial (IA) d'espècies d'interès productiu permet un major control sanitari i la creació de bancs de germoplasma d'alt valor genètic, entre d'altres avantatges. En el mercat porcí la major part de les inseminacions són encara realitzades amb semen refrigerat degut a l'èxit de l'aplicació de diluents de llarga durada i també a causa de la sensibilitat de l'esperma porcina a la criopreservació. Malgrat que aquesta sensibilitat ve donada per característiques particulars de la fisiologia espermàtica en l'espècie, algunes ejaculacions mantenen els paràmetres de qualitat espermàtica després de la criopreservació (ejaculacions amb bona "congelabilitat", GFEs) enfront d'altres que no sobreviuen al procés (ejaculacions amb mala "congelabilitat", PFEs). El primer objectiu de l'estudi va ser comparar ambdós grups en termes de fertilitat in vivo. El segon objectiu va ser testar l'eficiència de la inseminació postcervical (post-CAI) amb l'esperma criopreservada. El tercer objectiu va ser buscar predictors de la congelabilitat de les ejaculacions, tant en les GFEs com en les PFEs i en tres passos del procés de criopreservació (a 17ºC, a 5ºC i a 240 min postdescongelació). Aquest objectiu es va dur a terme mitjançant l'avaluació de paràmetres convencionals de qualitat espermàtica i a través de l'estudi de la localització i la reactivitat sota el microscopi de tres proteïnes (GLUT3, HSP90AA1 i Cu/ZnSOD) relacionades amb la fisiologia espermàtica i amb possibles rols en la congelabilitat. El quart objectiu va ser quantificar l'expressió de les tres proteïnes per transferència western, tant en espermatozoides d'ejaculacions GFEs com en els d'ejaculacions PFEs i en els tres passos abans esmentats, per tal de determinar el seu potencial com a predictores de la congelabilitat. Pel primer i el segon objectiu, 86 truges van ser inseminades per post-CAI amb 26 ejaculacions de mascles Piétrain dividides en una porció refrigerada a 17ºC (tractament control) i una porció criopreservada, ambdues porcions classificades alhora com a GFEs o PFEs. Els resultats més rellevants van demostrar que les probabilitats d'embaràs eren dues vegades menors en inseminacions amb esperma criopreservada d'ejaculacions PFEs (P < 0.05) que en inseminacions amb esperma criopreservada d'ejaculacions GFEs, fet que indica que les ejaculacions amb percentatges elevats d'espermatozoides mòbils progressius i d'integritat de membrana (per sobre del 40% en les GFEs) són més favorables a provocar embarassos que no pas aquelles ejaculacions amb una pobra funció espermàtica in vitro (PFEs). Ni el nombre de truges que van donar a llum, ni la quantitat de garrins, ni el risc de reflux espermàtic van ser significativament diferents entre les inseminacions amb esperma criopreservada d'ejaculacions GFEs i les inseminacions control amb semen refrigerat, la qual cosa demostra la bona aplicabilitat de la inseminació post-CAI amb l'esperma criopreservada. Finalment, pel tercer i quart objectius van ser criopreservades 29 i 11 ejaculacions de mascles Piétrain, respectivament. Dos paràmetres cinètics espermàtics, la linealitat (LIN) i la rectitud (STR), van mostrar una hiperactivació de la mobilitat superior en les ejaculacions PFEs que en les GFEs després de 30 min a 5ºC durant la criopreservació. A més, la combinació d'ambdós paràmetres va donar una fiabilitat propera al 72% en la predicció de la congelabilitat de les ejaculacions porcines. Tot i que no va ser possible predir la congelabilitat mitjançant l'avaluació de les tres proteïnes al microscopi, els resultats de transferència western van revelar diferències en l'expressió de la HSP90AA1 en l'esperma a 17ºC, molt possiblement relacionades amb la millor supervivència a la criopreservació dels espermatozoides d'ejaculacions GFEs. Aquests resultats suggereixen que la promoció de la criopreservació d'esperma porcina per la seva aplicació en IA passa pel desenvolupament de tests per la predicció de la congelabilitat en semen refrigerat.

Differentially transcribed genes in skeletal muscle of lambs

The objective of this study was to compare gene transcription profiles in Longissimus dorsi muscle of the following four hair sheep genetic groups, Morada Nova (MO), Brazilian Somali (SO), Santa Inĉs (SI) and 1/2 Dorper×1/2 Morada Nova (F1). These groups all display different postnatal muscle growth. The transcriptomes of the skeletal muscle of the lambs (at 200 days of age) were profiled by using oligonucleotide microarrays and reverse transcription-quantitative real-time PCR (RT-qPCR). The microarray experiment identified 262 transcripts that were differentially expressed when transcription levels were compared between the different breeds. A total of 23 transcripts among which those involved in skeletal muscle development (MyoD1 and IGFBP4), lipogenesis and adipogenesis (C/EBPδ, PPARγ and PGDS) were differentially expressed in at least in one comparison. Clustering analysis showed that there is greater similarity in gene expression between the MO and SI breeds and between F1 and SO genetic groups. The SO breed has the most distinct expression pattern. The RT-qPCR results confirmed the findings from the microarray study. A positive correlation was observed between the expression of MyoD1 and the cold carcass yield. The negative correlations between the weight and yield of cold carcass with the expression of C/EBPδ mean that the selection for adipogenesis could lead to a lower carcass weight. The GLUT3 and PYGL gene transcripts were negatively correlated with fat thickness, but ATP5G1 was positively correlated with this trait. Interestingly, many genes negatively correlated with PUFA were positively correlated with cold carcass yield. In conclusion, the present work demonstrated that there are breed-specific expression patterns in Brazilian hair sheep genetic groups. The differences in gene expression among genetic groups were consistent with their phenotypic differences. The positive correlation of the MyoD1 expression with the cold carcass yield suggests that this gene is important for tissue growth in sheep. The positive correlation of the C/EBPδ expression with PUFA provides an opportunity to select for lipid deposition in meat animals. © 2012 Elsevier B.V.

Functional and physiological role of vitamin C transporters

Vitamin C (ascorbic acid) is required for the synthesis of collagen, carnitine, catecholamine and the neurotransmitter norepinephrine. Vitamin C also plays an important role in protection against oxidative stress. Transporters for vitamin C and its oxidized form dehydroascorbate (DHA) are crucial to keep vitamin concentrations optimal in the body. The human SLC23 family consists of the Na(+)-dependent vitamin C transporters SVCT1 (SLC23A1) and SVCT2 (SLC23A2) and the orphan transporter SVCT3 (SLC23A3). Phylogenetically, the SLC23 family belongs to the nucleobase-ascorbate transporter family although no specificity for nucleobases has yet been demonstrated for the human members of this family. In fact, the SVCT1 and SVCT2 transporters are rather specific for ascorbic acid. SVCT1 is expressed in epithelial tissues such as intestine, where it contributes to the maintenance of whole-body ascorbic acid levels, whereas the expression of SVCT2 is relatively widespread either to protect metabolically active cells and specialized tissues from oxidative stress or to deliver ascorbic acid to tissues that are in high demand of the vitamin for enzymatic reactions. DHA, the oxidized form of ascorbic acid is taken up and distributed in the body by facilitated transport via members of the SLC2/GLUT family (GLUT1, GLUT3, and GLUT4). Although, the main focus of this review is on the SLC23 family of ascorbic acid transporters, transporters of DHA and nucleobases are also briefly discussed for completeness.