Affinage

SLC2A8

Solute carrier family 2, facilitated glucose transporter member 8 · UniProt Q9NY64

Length
477 aa
Mass
50.8 kDa
Annotated
2026-06-10
45 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC2A8 (GLUT8) is a facilitative hexose transporter that couples substrate uptake to cellular energy metabolism and nutrient-sensing across multiple tissues (PMID:10671487, PMID:24519932). It transports glucose with a Km of ~2 mM and additionally carries fructose and trehalose (PMID:10671487, PMID:24519932, PMID:27922102). The protein is normally retained on intracellular membranes—endosomes, lysosomes, and the endoplasmic reticulum—through an N-terminal [DE]XXXL[LI] dileucine targeting motif, and mutation of this motif redirects it to the plasma membrane (PMID:10671487, PMID:19176349). In hepatocytes GLUT8 mediates fructose uptake that drives de novo lipogenesis, and its loss attenuates hepatic triglyceride and cholesterol accumulation on a high-fructose diet (PMID:24519932). GLUT8 is also the carrier required for cytoplasmic entry of trehalose, which activates AMPK-dependent autophagy; this defect is rescued by heterologous expression of the Drosophila trehalose transporter Tret1 (PMID:27922102). In liver it further governs the adaptive fasting response by restraining the cell-autonomous PPARα–FGF21 axis, such that GLUT8 deficiency hyperactivates ketogenesis and FGF21 secretion (PMID:29596655). Consistent with a role in supporting cellular respiration, SLC2A8 loss impairs oocyte ATP production and decidualization, reduces sperm motility and mitochondrial membrane potential, and diminishes oxidative-phosphorylation transcriptional programs in trophoblast cells (PMID:19176349, PMID:22649075, PMID:38474355).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 High

    Established that SLC2A8 is a bona fide facilitative hexose transporter and defined its intracellular-retention mechanism, answering what biochemical activity the gene encodes.

    Evidence Xenopus oocyte radiolabeled transport assay, dileucine-motif mutagenesis, in vitro translation/glycosylation, and immunofluorescence in HEK293T

    PMID:10671487

    Open questions at the time
    • Did not establish the physiological substrate in mammalian tissues
    • Surface trafficking only achieved by motif mutation, not by a physiological signal
  2. 2001 Medium

    Showed that endogenous GLUT8 in brain is predominantly intracellular and neuron-restricted, addressing whether native localization matches the heterologous retention behavior.

    Evidence Subcellular fractionation/immunoblot and immunohistochemistry in rat hippocampus, including streptozotocin-diabetic rats

    PMID:11226324

    Open questions at the time
    • mRNA/protein discordance in diabetes left unexplained
    • No functional transport assay in neurons
  3. 2002 Medium

    Mapped cell-type-specific expression to differentiating spermatocytes and vasopressin neurons with vesicular/secretory-granule localization, suggesting tissue-specific secretory roles.

    Evidence Immunohistochemistry, double immunofluorescence, and immunogold labeling of cryosections in testis and brain

    PMID:11751619

    Open questions at the time
    • Functional consequence of dense-core-vesicle localization not tested
    • No substrate flux measured in these cell types
  4. 2009 Medium

    A knockout mouse linked GLUT8 loss to defined cellular phenotypes (sperm motility, mitochondrial potential/ATP, neuronal proliferation, cardiac conduction), connecting the transporter to energy metabolism in vivo.

    Evidence Slc2a8 knockout phenotyping (behavior, cardiac conduction, sperm analysis, mitochondrial membrane potential) plus heterologous localization

    PMID:19176349

    Open questions at the time
    • Mechanistic link between transport activity and each phenotype not resolved
    • Substrate driving sperm energetics not identified
  5. 2012 Medium

    Demonstrated that GLUT8 is required for oocyte ATP production and endometrial decidualization, establishing a reproductive role tied to cellular energetics.

    Evidence Slc2a8 knockout mouse with oocyte metabolic/ATP assays, decidualization assay, ovarian transplantation, and MRI body composition

    PMID:22649075

    Open questions at the time
    • Transported substrate underlying the oocyte/implantation defect not defined
    • Single lab
  6. 2014 High

    Identified hepatic fructose as a physiological substrate and linked GLUT8-mediated fructose uptake to de novo lipogenesis, providing a metabolic-disease-relevant function.

    Evidence Radiolabeled fructose uptake with overexpression and shRNA knockdown plus Slc2a8 KO mice on high-fructose diet with hepatic lipid quantification

    PMID:24519932

    Open questions at the time
    • Surface vs. intracellular site of fructose transport in hepatocytes not fully reconciled with earlier retention data
    • Insulin signaling unchanged, leaving the lipogenic mechanism partly open
  7. 2016 High

    Showed GLUT8 is the mammalian trehalose carrier required for trehalose-induced, AMPK-dependent autophagy, defining a signaling pathway downstream of transport.

    Evidence GC/MS and radiolabeled trehalose uptake, fluorescence microscopy, GLUT8-deficient hepatocytes/mice, AMPK/mTORC1 phosphorylation assays, and Tret1 reconstitution

    PMID:27922102

    Open questions at the time
    • How cytoplasmic trehalose activates AMPK not mechanistically resolved
    • Physiological source of trehalose in mammals unclear
  8. 2018 Medium

    Placed hepatic GLUT8 upstream of the PPARα–FGF21 fasting program, showing it restrains adaptive ketogenesis and lipid mobilization in a cell-autonomous manner.

    Evidence Slc2a8 KO fasting challenge with metabolic phenotyping, mitochondrial respiration, PPARα/FGF21 assays in vivo and in primary hepatocytes, and PPARα-knockdown epistasis

    PMID:29596655

    Open questions at the time
    • Mechanism connecting transport activity to PPARα activation not defined
    • Identity of the metabolic signal sensed by hepatocytes unknown
  9. 2024 Medium

    Established that in human trophoblast cells GLUT8 supports cellular respiration/oxidative phosphorylation rather than bulk glucose delivery, refining its functional role in the placenta.

    Evidence Lentiviral RNAi knockdown in ACH-3P cells with glucose uptake assay and RNAseq transcriptome analysis

    PMID:38474355

    Open questions at the time
    • Modest glucose-uptake reduction leaves the respiratory link correlative
    • Direct measurement of respiration not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLUT8 trafficking is physiologically regulated to expose its transport activity at the relevant membrane, and how intracellular substrate flux is mechanistically transduced into AMPK and PPARα signaling, remains unresolved.
  • No physiological signal shown to relieve dileucine-motif retention
  • Molecular link between transport and downstream kinase/nuclear-receptor signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2 R-HSA-1474165 Reproduction 1 R-HSA-9612973 Autophagy 1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 GLUTX1 (SLC2A8) is a facilitative glucose transporter with a Km of ~2 mM for glucose; transport activity was inhibited by cytochalasin B and partially competed by D-fructose and D-galactose when expressed in Xenopus oocytes. The protein contains an N-terminal dileucine internalization motif that retains it intracellularly; mutation of this motif redirected the protein to the cell surface. In vitro translated GLUTX1 migrates as a 35-kDa protein that becomes glycosylated in the presence of microsomal membranes. Xenopus oocyte expression with radiolabeled transport assay, site-directed mutagenesis of dileucine motif, in vitro translation with microsomal glycosylation, immunofluorescence microscopy in HEK293T cells The Journal of biological chemistry High 10671487
2002 GLUTX1 (SLC2A8) protein localizes in the testis to differentiating spermatocytes (type 1 stage) but is undetectable in mature spermatozoa. In the brain, it localizes specifically to vasopressin neurons (not oxytocin neurons) of the supraoptic nucleus, and immunogold labeling identified it in dense core vesicles of synaptic nerve endings and secretory granules of vasopressin-positive neurons. Immunohistochemistry, double immunofluorescence microscopy, immunogold labeling of ultrathin cryosections Endocrinology Medium 11751619
2001 GLUTx1 (SLC2A8) protein in rat hippocampus is primarily localized to the intracellular compartment with limited association with the plasma membrane, as determined by immunoblot analysis of hippocampal membrane fractions. Immunohistochemistry showed expression restricted to neuronal cell bodies and most proximal dendrites. In streptozotocin diabetic rats, GLUTx1 mRNA levels increased in pyramidal and granule neurons without a concomitant increase in protein levels. Subcellular fractionation with immunoblot, immunohistochemistry, quantitative autoradiography, single-cell emulsion autoradiography Proceedings of the National Academy of Sciences of the United States of America Medium 11226324
2009 GLUT8 (SLC2A8) constitutively associates with endosomes, lysosomes, and endoplasmic reticulum membranes via its N-terminal [DE]XXXL[LI] endosomal/lysosomal targeting motif. No conventional signal tested induced translocation of GLUT8 to the plasma membrane in heterologous expression systems. Knockout mice showed viable development but mild phenotypes including increased neuronal proliferation in dentate gyrus, hyperactivity, impaired atrial electrical conduction, and reduced sperm motility with decreased mitochondrial membrane potential and ATP levels in sperm. Heterologous overexpression with subcellular localization, Slc2a8 knockout mouse phenotyping (behavioral, cardiac, sperm analysis, mitochondrial membrane potential assay) American journal of physiology. Endocrinology and metabolism Medium 19176349
2014 GLUT8 (SLC2A8) is a cell surface-localized transporter in hepatocytes that mediates fructose uptake. GLUT8 overexpression significantly increased radiolabeled fructose uptake, while shRNA-mediated GLUT8 knockdown blocked it. GLUT8-deficient mice fed a high-fructose diet showed diminished hepatic fructose uptake, reduced de novo lipogenesis, and attenuated hepatic triglyceride and cholesterol accumulation without changes in insulin-stimulated Akt phosphorylation. Radiolabeled fructose uptake assay, shRNA knockdown, GLUT8 overexpression, Slc2a8 knockout mouse with high-fructose diet challenge, hepatic lipid quantification The Journal of biological chemistry High 24519932
2016 SLC2A8 (GLUT8) functions as a mammalian trehalose transporter required for trehalose-induced autophagy. GC/MS, fluorescence microscopy, and radiolabeled uptake studies demonstrated that trehalose traverses the plasma membrane via GLUT8. GLUT8-deficient hepatocytes and mice exposed to trehalose resisted trehalose-induced AMPK phosphorylation and autophagic induction. Although trehalose suppressed mTORC1 signaling, mTORC1 suppression alone was insufficient to activate autophagy in the absence of AMPK or GLUT8. Heterologous overexpression of Drosophila trehalose transporter-1 (Tret1) reconstituted autophagic flux and AMPK signaling defects in GLUT8-deficient hepatocytes. GC/MS trehalose quantification, fluorescence microscopy, radiolabeled uptake assay, GLUT8-deficient mouse and primary hepatocytes, AMPK/mTORC1 phosphorylation assays, Tret1 reconstitution experiment Scientific reports High 27922102
2012 SLC2A8 deficiency in mice impairs oocyte metabolism and ATP production, and causes defective decidualization of endometrial stromal cells required for embryo implantation. Ovarian transplantation studies confirmed that SLC2A8 loss affects both embryo and implantation processes. Null mice display decreased litter size, reduced postnatal growth, decreased body fat, and resistance to high-fat/high-carbohydrate diet. Slc2a8 knockout mouse (exons 1–4 deletion, protein expression confirmed by Western blot), oocyte metabolic/ATP assays, decidualization assay, ovarian transplantation, MRI body composition Biology of reproduction Medium 22649075
2018 Hepatocyte GLUT8 (SLC2A8) regulates the adaptive fasting response through the PPARα signaling cascade. Slc2a8-disrupted mice exhibited enhanced thermogenesis, ketogenesis, and peripheral lipid mobilization during fasting, with mildly impaired hepatic mitochondrial oxidative metabolism. Hepatic PPARα and its target FGF21 were cell-autonomously hyperactivated in GLUT8-deficient liver and primary hepatocytes during nutrient depletion. Hepatic PPARα knockdown in GLUT8-deficient mice normalized the enhanced ketogenic and FGF21 secretory responses. Slc2a8 knockout mouse fasting challenge, metabolic phenotyping (thermogenesis, ketogenesis, lipid mobilization), mitochondrial respiration assay, PPARα/FGF21 signaling assays in vivo and in primary hepatocytes, hepatic PPARα knockdown epistasis Endocrinology Medium 29596655
2024 SLC2A8 knockdown (79% mRNA reduction) in human first-trimester trophoblast cells (ACH-3P) caused an 11% reduction in glucose uptake. RNAseq identified 1525 differentially expressed transcripts, with enrichment in metabolic pathways associated with cellular respiration, oxidative phosphorylation, and ATP synthesis, indicating that SLC2A8's primary function in trophoblast cells is to support cellular respiration rather than net glucose delivery. Lentiviral RNAi knockdown in ACH-3P cells, glucose uptake assay, RNAseq transcriptome analysis, real-time qPCR validation Cells Medium 38474355

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy 338 30335591
2000 GLUTX1, a novel mammalian glucose transporter expressed in the central nervous system and insulin-sensitive tissues. The Journal of biological chemistry 189 10671487
2001 Intracellular organization of insulin signaling and GLUT4 translocation. Recent progress in hormone research 170 11237212
2000 Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes. The Biochemical journal 127 10970791
2021 Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response. Autophagy 116 33706671
2009 GLUT8, the enigmatic intracellular hexose transporter. American journal of physiology. Endocrinology and metabolism 96 19176349
2016 SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Scientific reports 92 27922102
2014 Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. The Journal of biological chemistry 85 24519932
2001 Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats. Proceedings of the National Academy of Sciences of the United States of America 83 11226324
2010 Adiponectin and adiponectin receptors in the mouse preimplantation embryo and uterus. Human reproduction (Oxford, England) 72 21106494
2008 Paternal effect on embryo quality in diabetic mice is related to poor sperm quality and associated with decreased glucose transporter expression. Reproduction (Cambridge, England) 72 18558660
2002 Immunolocalization of GLUTX1 in the testis and to specific brain areas and vasopressin-containing neurons. Endocrinology 61 11751619
2016 Fructose Synthesis and Transport at the Uterine-Placental Interface of Pigs: Cell-Specific Localization of SLC2A5, SLC2A8, and Components of the Polyol Pathway. Biology of reproduction 52 27535960
2012 Decreased spermatogenesis, fertility, and altered Slc2A expression in Akt1-/- and Akt2-/- testes and sperm. Reproductive sciences (Thousand Oaks, Calif.) 46 22228739
2009 Regulation of facilitative glucose transporters and AKT/MAPK/PRKAA signaling via estradiol and progesterone in the mouse uterine epithelium. Biology of reproduction 46 19208550
2012 Slc2a8 deficiency in mice results in reproductive and growth impairments. Biology of reproduction 34 22649075
2016 A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe. The Journal of physiology 33 27292274
2010 The effect of monosaccharide sugars and pyruvate on the differentiation and metabolism of sheep granulosa cells in vitro. Reproduction (Cambridge, England) 33 20634389
2022 Metabolic pathways utilized by the porcine conceptus, uterus, and placenta. Molecular reproduction and development 31 35460118
2016 Cyclic AMP Affects Oocyte Maturation and Embryo Development in Prepubertal and Adult Cattle. PloS one 30 26926596
2021 Pre-implantation exogenous progesterone and pregnancy in sheep. II. Effects on fetal-placental development and nutrient transporters in late pregnancy. Journal of animal science and biotechnology 28 33827696
2007 A set of genes previously implicated in the hypoxia response might be an important modulator in the rat ear tissue response to mechanical stretch. BMC genomics 25 18034909
2012 In vivo oocyte IGF-1 priming increases inner cell mass proliferation of in vitro-formed bovine blastocysts. Theriogenology 21 22538004
2020 Differential DNA methylation profile in infants born small-for-gestational-age: association with markers of adiposity and insulin resistance from birth to age 24 months. BMJ open diabetes research & care 17 33106332
2018 Expression of glucose transporters SLC2A1, SLC2A8, and SLC2A12 in different chicken muscles during ontogenesis. Journal of animal science 17 29401234
2022 Blood DNA Methylation Patterns in Older Adults With Evolving Dementia. The journals of gerontology. Series A, Biological sciences and medical sciences 16 35299244
2018 Enhanced Hepatic PPARα Activity Links GLUT8 Deficiency to Augmented Peripheral Fasting Responses in Male Mice. Endocrinology 15 29596655
2023 Transcriptome and Metabolome Analyses Reveal Sugar and Acid Accumulation during Apricot Fruit Development. International journal of molecular sciences 14 38069317
2013 Dynamic PET with (18)F-Deoxyglucose (FDG) and quantitative assessment with a two-tissue compartment model reflect the activity of glucose transporters and hexokinases in patients with colorectal tumors. American journal of nuclear medicine and molecular imaging 10 24116350
2024 Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer. Cancer science 8 39403788
2019 Multiple facilitated glucose transporters SLC2As are required for normal mouse preimplantation embryo development. American journal of translational research 8 31312354
2013 Transcript abundance and apoptosis in day-7 porcine blastocyst cultured with exogenous insulin-like growth factor-I. Reproductive biology 8 23522072
2014 Ovarian steroids influence cerebral glucose transporter expression in a region- and isoform-specific pattern. Journal of neuroendocrinology 7 24612045
2024 Tea Polyphenols Inhibit Methanogenesis and Improve Rumen Epithelial Transport in Dairy Cows. Animals : an open access journal from MDPI 6 39272354
2014 Stage specific expression of ATP-binding cassette and solute carrier superfamily of transporter genes in mammary gland of riverine buffalo (Bubalus bubalis). Animal biotechnology 6 24669870
2024 DNA Methylation Signatures in Paired Placenta and Umbilical Cord Samples: Relationship with Maternal Pregestational Body Mass Index and Offspring Metabolic Outcomes. Biomedicines 5 38397903
2014 Effect of monosaccharide sugars on LH-induced differentiation and sugar transport facilitator (SLC2A) expression in sheep theca cells in vitro. Reproduction, fertility, and development 5 23711112
2025 SRC involves in lysosomal function and regulates ferroptosis in polycystic ovary syndrome. Journal of ovarian research 4 40045372
2024 Biological hypoxia in pre-transplant human pancreatic islets induces transplant failure in diabetic mice. Scientific reports 4 38811610
2024 Methionine supply during mid-gestation modulates the bovine placental mTOR pathway, nutrient transporters, and offspring birth weight in a sex-specific manner. Journal of animal science 4 39390894
2024 The Impact of SLC2A8 RNA Interference on Glucose Uptake and the Transcriptome of Human Trophoblast Cells. Cells 3 38474355
2023 Identification of ferroptotic genes and phenotypes in idiopathic nonobstructive azoospermia. Systems biology in reproductive medicine 3 37782778
2026 Genetic and Environmental Architecture of Ram Fertility Traits: A Review. Genes 0 41751594
2025 Dietary intervention enhances fertility in obese male mice by regulating SLC2As. Journal of molecular histology 0 40425964
2025 Lysosome-derived biomarkers for predicting survival outcome in acute myeloid leukemia. Discover oncology 0 40751887

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