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GLUT5

GLUT5, also known as solute carrier family 2 member 5 (SLC2A5), is a fructose-specific facilitative transporter protein that enables the passive diffusion of fructose across plasma membranes, primarily facilitating the uptake of dietary fructose in the small intestine.^[1] As the only member of the glucose transporter (GLUT) family dedicated exclusively to fructose transport, it exhibits a Michaelis-Menten constant (Km) of approximately 6 mM for D-fructose and shows no affinity for glucose or galactose.^[1]^[2] Structurally, GLUT5 consists of 501 amino acids forming 12 transmembrane α-helices organized into an N- and C-terminal bundle, characteristic of the major facilitator superfamily (MFS) fold, with a molecular weight of about 55 kDa.^[1] It operates via a rocker-switch mechanism, where the bundles alternate between outward- and inward-facing conformations to bind and release fructose at the cell surface, with local gating mediated by transmembrane helices 7 and 10.^[2] Crystal structures of rat and bovine GLUT5, resolved at 3.2–3.3 Å, reveal a deep substrate-binding pocket involving conserved residues like Gln166 and Trp419, which confer fructose specificity.^[2] GLUT5 is predominantly expressed on the apical membrane of enterocytes in the jejunum of the small intestine, where it absorbs fructose from the lumen, with lower levels in the kidney (S3 proximal tubules), testis (spermatids), skeletal muscle, and other tissues like adipose and brain.^[1]^[3] Its expression is tightly regulated: in the intestine, it increases post-weaning and is induced by dietary fructose through transcription factors like ChREBP-MLX, as well as by hormones such as glucocorticoids and thyroid hormone, displaying a circadian rhythm.^[1]^[3] In the kidney and muscle, expression rises in response to hyperglycemia in diabetes, while in the testis, it supports sperm energy metabolism without strong substrate dependence.^[3] Dysregulation of GLUT5 contributes to various diseases; for instance, reduced GLUT5 expression or activity can contribute to fructose malabsorption syndromes, while overexpression promotes fructose-fueled proliferation and metastasis in cancers like colorectal and breast carcinoma.^[1]^[3] In metabolic disorders such as obesity and type 2 diabetes, altered GLUT5 activity exacerbates fructose metabolism, potentially linking high-fructose diets to hypertension and insulin resistance.^[3] Recent studies as of 2025 have explored inhibiting GLUT5 to alleviate high-fructose diet-induced metabolic dysfunction-associated steatotic liver disease and engineering GLUT5-targeted CAR T-cells for cancer immunotherapy.^[4]^[5] Emerging applications include targeting GLUT5 for cancer therapies and positron emission tomography (PET) imaging using 18F-labeled fructose analogs.^[1]

Gene

Genomic Location and Organization

The SLC2A5 gene, which encodes the GLUT5 protein, is located on the short arm of human chromosome 1 at position 1p36.23, spanning approximately 53 kb from base pair 9,035,106 to 9,088,478 on the reverse strand according to the GRCh38 assembly.^[6] This positioning places it within a region associated with various genetic disorders, though SLC2A5 itself is primarily linked to fructose transport functions. The gene structure includes 13 exons, with the first exon containing a 5' untranslated region (UTR) followed by the start of the coding sequence, and the remaining 12 exons completing the 501-amino-acid protein.^[7]^[8] The organization of SLC2A5 features well-defined intron-exon boundaries, with studies analyzing at least 20 bp flanking each junction to identify variants; for instance, introns 5–9 have been fully sequenced in genomic clones, revealing variable lengths that contribute to the overall 53 kb span.^[9] The proximal promoter region, approximately 700 bp upstream of the transcription start site, regulates tissue-specific expression and has been implicated in transcriptional control mechanisms, including responses to dietary sugars.^[10] Alternative splicing generates multiple transcripts, with the canonical isoform utilizing most exons to produce a 501-amino-acid protein, while shorter variants omit certain coding regions.^[11] Known genetic variants in SLC2A5 predominantly occur in noncoding regions, such as the promoter and introns. These variants have been associated with modest effects on metabolic phenotypes, including alterations in insulin sensitivity and lipid profiles in hypertensive individuals, potentially influencing gene stability or expression levels through regulatory impacts.^[12] Although some studies suggest limited contribution to conditions like fructose malabsorption, certain noncoding SNPs may modulate promoter activity, affecting mRNA stability or transcription efficiency. Rare loss-of-function variants have been linked to essential fructosuria, a benign condition of fructose excretion in urine.^[7]^[13] Evolutionary conservation of SLC2A5 across mammals underscores its functional importance, with orthologs identified in over 250 species, including mice, rats, cows, and primates, exhibiting high sequence similarity in coding exons (typically >85% identity). Key conserved sequences include the exon-intron boundaries critical for splicing and regulatory elements in the promoter region that maintain fructose-responsive expression patterns. This conservation extends to syntenic regions on chromosome 1, preserving genomic architecture from early mammals to humans.

Expression Patterns

GLUT5, encoded by the SLC2A5 gene, exhibits its highest expression in the jejunum of the small intestine, particularly on the apical membrane of enterocytes, facilitating fructose absorption. Lower levels of expression are detected in several other tissues, including the kidney (primarily in the proximal tubules), brain (notably in microglia and certain neuronal populations), testis (in Sertoli cells), adipose tissue (adipocytes), and skeletal muscle (sarcolemma).^[3]^[14]^[15] During development, SLC2A5 expression undergoes significant upregulation in the small intestine coincident with weaning in both rodents and humans, aligning with the transition to a diet containing fructose. In rats, GLUT5 mRNA and protein levels remain low during mid-weaning (around 14-21 days postnatal) but increase markedly by 28 days, reaching adult-like patterns that support enhanced fructose uptake. This developmental induction occurs independently of dietary fructose initially but is potentiated by its introduction, ensuring adaptation to post-weaning nutrition. Similar patterns are observed in humans, where intestinal GLUT5 expression rises post-weaning to accommodate fruit and sucrose consumption.^[3]^[15] SLC2A5 expression is highly inducible by dietary fructose across species. In the rodent intestine, high-fructose feeding elevates GLUT5 mRNA and protein levels, with fold-changes typically ranging from 2- to 5-fold in both suckling and adult animals, enhancing fructose transport capacity. For instance, in weaning rats exposed to fructose-enriched diets, intestinal GLUT5 mRNA increases 3- to 5-fold, while in adults, a similar diet induces 2- to 3-fold elevations in mRNA and up to 5-fold in protein abundance. These changes occur rapidly, often within days, and involve transcriptional activation responsive to luminal fructose signaling.^[3]^[16]^[17] Notable species differences exist in tissue-specific expression profiles. While both humans and rats show prominent intestinal expression, renal GLUT5 mRNA levels are higher in rats compared to humans, reflecting potentially greater fructose reabsorption capacity in rodent kidneys. This disparity underscores variations in fructose handling across mammals, with rat models often displaying amplified renal responses to dietary manipulations.^[3]^[15]

Protein Structure

Primary and Secondary Structure

The GLUT5 protein, encoded by the SLC2A5 gene, comprises 501 amino acids and has a molecular weight of approximately 55 kDa. Its primary structure includes hydrophilic N- and C-terminal domains oriented toward the cytoplasm, which flank the core transmembrane region.^[18]^[19] The secondary structure of GLUT5 features 12 transmembrane alpha-helices (TM1–TM12) that span the plasma membrane, connected by six intracellular loops and five extracellular loops, forming the characteristic major facilitator superfamily (MFS) fold adapted for monosaccharide transport.^[20]^[21] Key structural motifs in GLUT5 include N-linked glycosylation sites, such as the consensus sequence at Asn51 in the first extracellular loop between TM1 and TM2, which contributes to protein maturation and stability.^[22] Additionally, conserved motifs like the sugar transporter signatures (e.g., PESPR and QLS motifs) are present in the transmembrane domains, facilitating substrate recognition.^[22] GLUT5 exhibits approximately 40% amino acid sequence identity with GLUT2, another fructose-transporting member of the GLUT family, while sharing lower overall homology with glucose-preferring isoforms; fructose-specific residues in human GLUT5, such as Gln167, Ile170, Ile174, Gln288, Gln289, Asn325, and Trp420 in the central binding cavity, distinguish its substrate selectivity.^[23]^[24]

Tertiary Structure and Topology

GLUT5 belongs to the major facilitator superfamily (MFS) of transporters, characterized by a conserved tertiary structure consisting of two bundles of six transmembrane α-helices each (TM1–6 and TM7–12), forming a central hydrophilic cavity that serves as the substrate translocation pathway.^[2] This architecture is typical of MFS proteins, with the N- and C-terminal bundles connected by a long intracellular loop and flanked by five additional intracellular helices (ICH1–5) that stabilize the cytoplasmic domain.^[2] Crystal structures from rat GLUT5 in the outward-open conformation (PDB: 4YBQ, 3.3 Å) and bovine GLUT5 in the inward-open conformation (PDB: 4YB9, 3.2 Å refined to 4.0 Å anisotropically) reveal these bundles adopting symmetrical, pseudo-twofold rotational symmetry, enabling alternating access to the binding site; these structures from rat and bovine orthologs (~90% sequence identity to human) inform the human GLUT5 topology.^[2] The topology of GLUT5 features 12 transmembrane helices traversing the lipid bilayer, with the amino (N) terminus and carboxyl (C) terminus both facing the cytoplasm, consistent with the canonical MFS fold.^[2] Each helix bundle undergoes rigid-body rocking motions relative to the other in a rocker-switch mechanism, transitioning between outward- and inward-facing states to facilitate substrate passage without direct ATP hydrolysis.^[2] Local gating elements, such as broken half-helices in TM7 and TM10, contribute to asymmetric rearrangements that control access to the central cavity.^[2] Insights into the fructose-binding site within this topology come from the crystal structures, which identify key polar residues lining the cavity, including Gln166 (TM5, equivalent to Gln167 in human), Asn324 (TM7, equivalent to Asn325), Gln287 and Gln288 (both TM7, equivalent to Gln288 and Gln289), which form hydrogen bonds with the hydroxyl groups of fructose.^[2] Additional hydrophobic residues like Ile169, Ile173 (TM5, equivalent to Ile170 and Ile174 in human), and Trp419 (equivalent to Trp420) further shape the site to accommodate the bulkier furanose or pyranose forms of fructose.^[2] Homology models based on these structures, combined with molecular dynamics simulations, confirm the conservation of this binding pocket across mammalian GLUT5 orthologs and highlight adaptations for fructose selectivity, such as a larger cavity compared to glucose-specific homologs like GLUT1.^[25]

Function

Transport Mechanism

GLUT5 facilitates the transport of fructose across cell membranes through a passive, energy-independent process known as facilitated diffusion, operating via the alternating access model. In this mechanism, the transporter alternates between outward-facing and inward-facing conformations, allowing fructose to bind on one side of the membrane and be released on the other without direct energy input such as ATP hydrolysis or coupling to ion gradients. The driving force is solely the concentration gradient of the substrate, enabling net flux from higher to lower fructose concentrations. This distinguishes GLUT5 from active transporters and underscores its role as a uniporter specific to fructose.^[2] The core of the transport cycle follows a rocker-switch mechanism, wherein the N- and C-terminal transmembrane helical bundles of GLUT5 undergo a rigid-body rotation of approximately 15 degrees upon fructose binding, transitioning from an outward-open to an inward-open state. This global conformational change is complemented by local gating movements in transmembrane helices 7 and 10, which help seal the pathway and prevent non-specific leakage. The affinity of GLUT5 for D-fructose is characterized by a Michaelis constant (Km) of approximately 10-15 mM (reported values range from 6-15 mM across species and assays), indicating high-affinity transport suitable for physiological fructose levels in the intestinal lumen. Experimental measurements using tryptophan fluorescence quenching in purified GLUT5 confirm this Kd value in the range of 6-9 mM.^[2]^[1]^[15] Central to the binding and translocation process are specific amino acid residues within the central substrate-binding cavity that coordinate the hydroxyl groups of fructose. For instance, asparagine at position 324 (Asn324) forms hydrogen bonds with the substrate, stabilizing its furanose or pyranose ring conformations, while a GLUT5-specific histidine residue (His386) in transmembrane helix 10 contributes to selectivity by interacting with fructose and gating elements like tyrosine in helix 7. These interactions, conserved among fructose transporters but distinct from glucose-binding sites in other GLUT isoforms, ensure efficient recognition and movement of fructose through the occluded intermediate state to the release site. Mutations in these residues, such as in Trp419, abolish transport activity, highlighting their essential role.^[2]^[25] Unlike some solute carriers, GLUT5-mediated transport is independent of pH variations and membrane voltage, operating effectively across a wide physiological range without proton or sodium co-transport. This pH and voltage insensitivity, combined with the absence of any ion or ATP coupling, allows GLUT5 to function solely as a bidirectional facilitator, equilibrating fructose across membranes based on its gradient alone. Such properties make it particularly adapted for absorptive epithelia where rapid, unregulated uptake is advantageous.^[2]

Substrate Specificity

GLUT5 demonstrates a high degree of substrate specificity for D-fructose among hexose sugars, serving as the primary facilitative transporter for this monosaccharide in mammalian cells. The affinity for D-fructose is notably higher than for other common sugars, with a reported Michaelis constant (Km) of approximately 10-15 mM (reported values range from 6-15 mM across species and assays) in human GLUT5, reflecting efficient uptake at physiological concentrations. In contrast, GLUT5 exhibits no significant transport activity for glucose or galactose, rendering D-fructose its optimal and predominant substrate. Additionally, GLUT5 does not transport disaccharides such as sucrose, limiting its role to monosaccharide facilitation.^[1]^[15] The molecular basis of this specificity lies in the structure of GLUT5's substrate-binding site, which preferentially accommodates the ketohexose configuration of D-fructose. Key interactions occur between the transporter's binding pocket and the hydroxyl groups at the C3 and C4 positions of fructose, enabling selective recognition in both furanose and pyranose ring forms. These interactions, involving residues such as Gln167, Asn325, and Trp420, stabilize fructose binding while excluding aldose sugars like glucose, which lack the appropriate stereochemistry for effective engagement.^[26]^[1] Competitive inhibition studies further illustrate GLUT5's selectivity, with glucose acting as a weak inhibitor of fructose transport, as glucose competes poorly for the binding site, consistent with the much lower transport rate for glucose compared to fructose. In comparison to other glucose transporters, such as GLUT2, which displays broad substrate specificity and moderate affinity for both glucose and fructose, GLUT5 effectively excludes glucose, highlighting its specialized role in fructose-selective transport.^[27]^[28]^[29]

Physiological Roles

Role in Fructose Absorption

GLUT5, a fructose-specific facilitative transporter, is primarily localized to the apical membrane of enterocytes in the jejunum, where it mediates the uptake of dietary fructose from the intestinal lumen into the epithelial cells. This apical positioning allows GLUT5 to selectively transport fructose across the brush border membrane via facilitated diffusion, driven by the concentration gradient established by luminal fructose from ingested food. In coordination with GLUT2, which is expressed on the basolateral membrane of the same enterocytes, GLUT5 enables transcellular transport of fructose: after entry via GLUT5, fructose diffuses out of the cell into the portal bloodstream through the lower-affinity, bidirectional GLUT2 transporter. This coupled mechanism ensures efficient vectorial transfer of fructose from the diet to systemic circulation, with GLUT5 serving as the rate-limiting step due to its higher specificity and affinity for fructose (Km ≈ 6 mM) compared to GLUT2 (Km ≈ 17 mM for fructose).^[3] In adult humans and rodents, GLUT5 accounts for the majority of intestinal fructose absorption, contributing to approximately 75-90% of uptake capacity under physiological conditions, as evidenced by studies showing drastic reductions in jejunal fructose transport and serum fructose levels in GLUT5 knockout models. This essential role becomes prominent post-weaning, when GLUT5 expression and transport activity increase 2- to 3-fold in the small intestine, adapting to the introduction of fructose-containing solid foods and preventing malabsorption in neonates where baseline levels are low. The transporter's capacity scales with dietary fructose exposure, upregulating to handle typical adult intakes of 50-100 g/day without overload, thereby maintaining homeostasis in fructose flux across the intestinal epithelium.^[28]^[3]^[30] Following absorption, fructose interacts with key metabolic enzymes within enterocytes, including ketohexokinase (KHK), which rapidly phosphorylates it to fructose-1-phosphate for subsequent cleavage by aldolase B into glycolytic intermediates; this initial metabolism supports energy production and signals feedback upregulation of GLUT5 to match influx rates. Although hexokinase can contribute minimally to fructose phosphorylation in some contexts, KHK dominates in the intestine, linking transport to local fructolysis and preventing intracellular fructose buildup that could inhibit further uptake. Under high-fructose loads (e.g., 50-100 g/day), this coordinated transport-metabolism axis sustains absorption rates of approximately 0.1 mmol/h per gram of mucosal protein in rodent models, ensuring efficient handling without metabolic bottlenecks.^[31] By facilitating near-complete fructose clearance from the lumen, GLUT5 plays a critical role in averting osmotic imbalances: unabsorbed fructose would otherwise retain water via osmosis, leading to luminal distension, bacterial fermentation, and diarrhea as seen in malabsorption syndromes. This protective function underscores GLUT5's integration into broader intestinal physiology, where its activity aligns with water and electrolyte absorption to promote overall digestive efficiency and prevent gastrointestinal distress from dietary sugars.^[32]

Expression and Function in Other Tissues

GLUT5 is expressed in the S3 segment of the proximal tubules in the kidney, where it localizes to the apical membrane of epithelial cells to facilitate the reabsorption of filtered fructose from the glomerular filtrate.^[33] This transport contributes to the renal handling of fructose, preventing its excessive urinary excretion and supporting local metabolism within tubular cells, although the exact proportion reabsorbed varies with dietary intake and plasma levels.^[34] In conditions of high fructose filtration, such as after dietary consumption, GLUT5-mediated uptake helps maintain systemic fructose homeostasis by contributing to the reabsorption of filtered fructose, with the remainder metabolized intracellularly via ketohexokinase.^[35] In the brain, GLUT5 is predominantly expressed in microglia and to a lesser extent in neurons, including cerebellar Purkinje cells, where it serves as a high-affinity fructose transporter with minimal glucose affinity.^[36] This expression enables fructose sensing and uptake in these cells, potentially modulating microglial activation during inflammatory or ischemic events; for instance, inhibiting GLUT5 in microglia has been shown to attenuate brain injury in models of ischemia by altering fructose metabolism and reducing pro-inflammatory responses.^[37] Additionally, short-term fructose exposure can upregulate GLUT5 in neuronal-astrocyte co-cultures, suggesting a role in neuroprotection or adaptive metabolic responses to dietary fructose fluctuations.^[38] GLUT5 is highly expressed in the testis, particularly in Leydig cells, germ cells, and spermatozoa, where it supports fructose uptake essential for spermatogenesis and sperm maturation.^[39] Fructose, transported via GLUT5, serves as a primary energy substrate for spermatozoa motility and maturation processes, with genetic disruption of Glut5 leading to reduced intratesticular fructose levels and impaired fertility in mouse models.^[40] In human testis, GLUT5 mRNA and protein are abundant in spermatozoa, underscoring its conserved role in providing metabolic support during gamete development.^[41] In adipose tissue, GLUT5 is expressed in adipocytes and pre-adipocytes, where it facilitates fructose entry to promote lipogenesis and adipocyte differentiation.^[10] This transporter contributes to fat accumulation by enabling fructose-driven activation of lipogenic pathways, including increased expression of enzymes like fatty acid synthase, particularly in response to high-fructose diets that upregulate GLUT5 and exacerbate obesity-related adipose expansion.^[42] In obesity models, such as Glut5 knockout mice, reduced GLUT5 expression leads to lower adiposity in epididymal white adipose tissue, highlighting its role in supporting de novo lipogenesis and leptin production from fructose metabolism. Skeletal muscle expresses GLUT5 at lower levels compared to other tissues, but its presence allows for local fructose utilization, particularly under metabolic stress conditions like exercise or diabetes.^[43] During physical activity or in diabetic states, upregulated GLUT5 may enhance fructose uptake to supplement energy demands or mitigate hyperglycemia by diverting alternative substrates away from glucose-dependent pathways, though direct evidence remains limited to fructose-enriched diet models showing persistent metabolic adaptations in muscle tissue.^[44] This function aids in maintaining muscle bioenergetics when fructose availability increases, contributing to overall tissue resilience in dysmetabolic environments.^[45]

Regulation

Transcriptional Regulation

The transcription of the SLC2A5 gene, encoding GLUT5, is primarily regulated in the small intestine through specific promoter elements that respond to carbohydrate-responsive transcription factors. The promoter region contains carbohydrate response elements (ChoREs), such as the sequence at -2165 to -2149 bp, which bind carbohydrate response element-binding protein (ChREBP). ChREBP activation by fructose metabolites directly upregulates SLC2A5 transcription, enhancing GLUT5 expression to facilitate increased fructose uptake.^[46] High-fructose diets induce rapid transcriptional activation of SLC2A5 via ChREBP, resulting in significant elevations in GLUT5 mRNA levels within hours to days. Studies in rodent models demonstrate that switching to a high-fructose diet can increase intestinal GLUT5 mRNA abundance by 3- to 12-fold, depending on the duration and model, thereby boosting fructose absorption capacity. This dietary regulation is specific to fructose and does not occur with equivalent glucose loads.^[3]^[47] Developmental regulation of SLC2A5 occurs during enterocyte differentiation, mediated by the caudal-type homeobox 2 (CDX2) transcription factor, which binds to specific sites in the promoter region shared between intestinal and kidney expression. CDX2 promotes basal SLC2A5 transcription as enterocytes mature, aligning GLUT5 expression with the functional differentiation of the intestinal epithelium. This mechanism ensures appropriate fructose transport capacity post-weaning.^[3] GLUT5 expression is also induced by hormones such as glucocorticoids and thyroid hormone. Additionally, it displays a circadian rhythm in the intestine.^[1]

Post-Translational Regulation

GLUT5 undergoes N-linked glycosylation at asparagine residue 51 in the extracellular loop between transmembrane helices 9 and 10, a modification characteristic of class II glucose transporters that contributes to proper protein folding, stability, and trafficking to the plasma membrane.^[26] This glycosylation site is conserved among GLUT5 orthologs and is essential for the transporter's maturation in the endoplasmic reticulum and Golgi apparatus before apical membrane insertion in polarized epithelial cells such as enterocytes.^[26] Phosphorylation modulates GLUT5 localization and activity, particularly through the PI 3-kinase/Akt signaling pathway, which mediates fructose-induced insertion of the transporter into the apical plasma membrane of intestinal epithelial cells, enhancing fructose uptake.^[3] In insulin-sensitive tissues like skeletal muscle and adipose tissue, insulin increases GLUT5 expression via promoter activation and kinase-dependent mechanisms, thereby facilitating fructose clearance from circulation.^[26] Although direct phosphorylation sites on GLUT5 remain to be fully characterized, these pathways underscore the role of reversible phosphorylation in regulating membrane abundance without altering total protein levels. GLUT5 trafficking involves Rab11a-dependent endosomal pathways in intestinal epithelial cells, where fructose uptake and subsequent metabolism via ketohexokinase trigger the recruitment of GLUT5-containing vesicles to the apical membrane, increasing surface expression by up to 10-fold.^[48] Under low-fructose conditions, reduced metabolic signaling limits this exocytic trafficking, leading to decreased apical localization and potentially favoring retrieval or internalization via endocytic mechanisms to maintain cellular homeostasis.^[48] While a dileucine motif has not been directly implicated in GLUT5 endocytosis, clathrin-mediated pathways observed in related GLUT family members suggest analogous recycling dynamics for GLUT5 in response to substrate availability.^[26] Ubiquitination targets GLUT5 for proteasomal degradation, as evidenced by lipopolysaccharide (LPS)-induced downregulation in rabbit enterocytes, where inhibition of the proteasome prevents loss of transporter levels and preserves fructose uptake capacity.^[3] This modification regulates protein turnover, allowing rapid adaptation to dietary fructose fluctuations.

Clinical Significance

Involvement in Metabolic Disorders

GLUT5 expression is upregulated in individuals with type 2 diabetes and obesity, contributing to increased intestinal fructose absorption and subsequent hepatic steatosis through enhanced fructose flux to the liver. In type 2 diabetic patients, duodenal GLUT5 mRNA and protein levels increase three- to fourfold compared to healthy controls, facilitating greater fructose uptake and metabolism that exacerbates insulin resistance and lipid accumulation in the liver. Similarly, enhanced intestinal GLUT5 expression is observed in obese and overweight individuals, promoting excessive fructose delivery to hepatocytes and correlating with the development of nonalcoholic fatty liver disease via uncontrolled fructolysis and lipogenesis.^[3]^[10]^[1] Although the SLC2A5 gene, which encodes GLUT5, has been investigated for a role in fructose malabsorption syndromes, studies have not identified coding region mutations in patients with isolated fructose malabsorption, suggesting that impaired intestinal fructose transport and associated symptoms such as bloating, diarrhea, and abdominal pain after fructose ingestion are due to other factors. These findings distinguish fructose malabsorption from benign conditions like essential fructosuria, which involves defects in downstream metabolism rather than transport.^[49]^[32] GLUT5 plays a key role in fructose-induced hypertension through its facilitation of fructose entry into cells, activating the ketohexokinase axis and promoting uric acid production. Fructose metabolism via ketohexokinase depletes ATP, elevates AMP, and drives purine degradation to uric acid, which contributes to endothelial dysfunction and elevated blood pressure. Studies in GLUT5 knockout models show attenuated hypertension in response to high-fructose diets, confirming the transporter's necessity in this pathway, particularly when combined with high salt intake.^[28]^[10]^[50] In inflammatory bowel disease (IBD), GLUT5 expression is elevated in the lamina propria of the large intestine, influencing vascular and lymphatic growth that may compromise gut barrier integrity. High GLUT5 levels in IBD patients promote angiogenesis and lymphangiogenesis, potentially exacerbating inflammation and permeability issues in the intestinal mucosa. Conversely, reduced GLUT5 expression in ileal Crohn's disease correlates with worsened colitis severity upon fructose exposure, highlighting its dual role in modulating dietary fructose's impact on barrier function.^[1]^[51]

Role in Cancer and Therapeutic Targeting

GLUT5 is overexpressed in multiple cancer types, including breast, prostate, and colorectal cancers, where it enhances fructose uptake to fuel glycolysis and support tumor proliferation. In colorectal cancer, GLUT5 mRNA levels are elevated approximately 2.5-fold in tumor tissues compared to adjacent healthy mucosa, enabling fructose-dependent metabolic reprogramming that drives cell growth.^[52] Similar overexpression occurs in prostate cancer specimens, where GLUT5 facilitates dietary fructose utilization to promote oncogenesis and metastasis.^[53] In breast cancer cells, high GLUT5 expression supports fructose metabolism under hypoxic conditions, contributing to survival and aggressive phenotypes.^[54] Elevated GLUT5 expression is associated with adverse clinical outcomes across various malignancies. In ovarian cancer, studies have linked high GLUT5 levels to increased tumor malignancy, enhanced metastatic potential, and poorer progression-free survival, highlighting its role as a prognostic biomarker.^[55] This correlation extends to other cancers, where GLUT5 upregulation signifies advanced disease and reduced patient survival rates.^[56] As a key mediator of tumor fructose metabolism, GLUT5 represents a promising therapeutic target. Virtual screening of chemical libraries in 2016 identified potent inhibitors, such as N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA), which specifically block GLUT5-mediated transport and suppress proliferation in fructose-dependent cancer cells.^[57] Preclinical investigations demonstrate that GLUT5 blockade disrupts glycolysis, inhibits migration and invasion, and reduces tumor growth in models of breast and colorectal cancers.^[58] Radiolabeled fructose analogs targeting GLUT5 enable non-invasive diagnostic imaging of fructose-avid tumors. The positron emission tomography (PET) tracer 6-deoxy-6-[18F]fluoro-D-fructose (6-[18F]FDF) selectively accumulates in GLUT5-expressing malignancies, such as breast cancer, providing a complementary tool to glucose-based FDG-PET for improved detection and staging.^[59] Ongoing developments in GLUT5-specific radiotracers aim to enhance specificity for fructose-metabolizing tumors.^[60]

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Jun 26, 2020 · GLUT5 is a fructose transporter with higher affinity for fructose than glucose [29, 207] and is abundant in the small intestine, kidney and ...
[26]
Health implications of fructose consumption: A review of recent data
It has been considered that moderate fructose consumption of ≤50g/day or ~10% of energy has no deleterious effect on lipid and glucose control and of ≤100g/day ...
[27]
Fructose-induced increases in expression of intestinal fructolytic and ...
Diet-induced specific increases in GLUT5 expression enhance the rate of fructose absorption and involve de novo mRNA and protein synthesis (25, 44).
[28]
Fructose malabsorption | Molecular and Cellular Pediatrics | Full Text
Feb 16, 2016 · Since GLUT5 represents the main intestinal fructose transporter, its involvement in the pathophysiology of fructose malabsorption seems obvious.<|control11|><|separator|>
[29]
Presence of fructose transporter GLUT5 in the S3 proximal tubules ...
GLUT5 is an isoform of the facilitated-diffusion glucose transporter family13, which transports fructose and is expressed in the small intestine, kidney, and ...
[30]
Na(+)-dependent fructose transport via rNaGLT1 in rat kidney
Although GLUT5 has been thought to play a primary role in renal fructose reabsorption in the brush-border membranes, it is localized only in the S3 segment, ...
[31]
Profiling Cell Heterogeneity and Fructose Transporter Expression in ...
Recent calculations have estimated that, on average, healthy human kidneys filter 4 to 25 g of fructose per day, an amount corresponding to ~8% of the filtered ...
[32]
Brain Metabolism - an overview | ScienceDirect Topics
GLUT5 acts as a fructose transporter in the brain with low affinity for glucose , and is primarily expressed in microglia , cerebellar Purkinje cells ...
[33]
https://www.sciencedirect.com/science/article/pii/S008525381546380X
[34]
Short-term fructose ingestion affects the brain independently from ...
After 1 week of fructose treatment (5 mM), GLUT5 levels were increased in culture containing both neurons and astrocytes, suggesting that either astrocytes ...
[35]
Mice Lacking the Fructose Transporter Glut5 Exhibit Excessive ...
Feb 5, 2025 · Glut5 expression was shown in Leydig cells and germ cells, from primary spermatocytes to spermatozoa. We found reduced intratesticular fructose ...Missing: maturation | Show results with:maturation
[36]
Inhibiting the fructose transporter GLUT5 boosts testosterone ...
Sep 12, 2025 · It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the Glut5 gene in male mice impairs spermatogenesis ...Missing: maturation | Show results with:maturation
[37]
Fructose transporter in human spermatozoa and small intestine is ...
GLUT5 exhibits selectivity for fructose transport, as determined by inhibition studies, with a Km of 6 mM. In addition, fructose transport by GLUT5 is not ...
[38]
The impact of dietary fructose on gut permeability, microbiota ...
GLUT5 transports only fructose, but GLUT2 both glucose and fructose as well as galactose. The intestinal fructose absorption is increased in the coingestion ...
[39]
Glucose Transporter 5 - an overview | ScienceDirect Topics
GLUT5 is defined as a facilitative glucose transporter and the most recent member of the glucose transporter gene family, consisting of 501 amino acids and ...
[40]
Skeletal muscle insulin resistance and adipose tissue hypertrophy ...
Most metabolic changes elicited by fructose-rich diet in skeletal muscle and epididymal adipose tissue persisted after switching to control diet.Missing: exercise | Show results with:exercise
[41]
Molecular aspects of fructose metabolism and metabolic disease
Dec 7, 2021 · Although GLUT5 expression is responsible for intestinal fructose absorption, it is also expressed in other tissues and cell types, including ...
[42]
Recent insights into the role of ChREBP in intestinal fructose ... - NIH
Recently, we have reported that ChREBP is a key transcription factor in fructose-mediated upregulation of fructose transporter (Glut5), fructolytic enzymes ( ...
[43]
Expression of the fructose transporter GLUT5 in patients with ...
Aug 7, 2025 · ... fructose) diet for 14 weeks, Glut5(-/-) mice did not display ... A 12-fold increase in GLUT5 mRNA levels was detected at the end of ...
[44]
Comparative Effects of Fructose and Glucose on Lipogenic Gene ...
Increasing the UDP-GlcNAc pool results in enhanced O-linked glycosylation of transcription factors, such as Sp-1, involved in the regulation of gene expression ...
[45]
Transport, metabolism, and endosomal trafficking‐dependent ...
Jun 12, 2015 · Dietary fructose specifically up-regulates GLUT5 mRNA and protein synthesis, leading to increased rates of fructose absorption (17).
[46]
Molecular analysis of the fructose transporter gene (GLUT5) in ...
Functional properties and tissue distribution of GLUT5 suggest that IFM might be due to mutations in the GLUT5 gene. To test this hypothesis, we screened the ...Missing: SLC2A5 essential fructosuria p. Thr109Ile
[47]
Ketohexokinase-Dependent Metabolism of Fructose Induces ... - NIH
Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through ...
[48]
Multilayered Interplay Between Fructose and Salt in Development of ...
Dec 31, 2018 · The development of hypertension in response to fructose and salt requires an intact Glut5 system, as elevated BP does not occur in Glut5 ...Missing: ketohexokinase axis
[49]
GLUT5 is a determinant of dietary fructose-mediated exacerbation of ...
Aug 1, 2021 · This study provides the first evidence that reduced levels of GLUT5, the fructose transporter, worsen experimental colitis upon fructose feeding.