Human Transporters

GLUT9New

GLUT9 (Glucose transporter type 9)

Aliases: URATv1 (voltage-driven urate transporter 1), UAQTL2, GLUTX

Gene name: Solute carrier family 2 member 9 (SLC2A9)

Summary

GLUT9, a member of the facilitated glucose transporter family, is a voltage-dependent urate transporter with a not yet fully elucidated role in uric acid homeostasis. In humans its most studied function is in the efflux of reabsorbed uric acid from the proximal tubule cells of the kidney toward the blood. While high levels of uric acid in the blood have been linked to gout, hypertension, cardiovascular diseases and metabolic syndrome, uric acid has strong antioxidant properties and was suggested to be a neuroprotective agent. To this day the only known substrate of GLUT9 is uric acid, and while it was originally shown to transport glucose and fructose, this transport activity was very low and the results were not always reproducible. It was even proposed that it might behave as an exchange transporter, exchanging uric acid for glucose and fructose, but this claim was not examined by other studies. Known inhibitors of GLUT9 include the uricosuric drug benzbromarone and the angiotensin II receptor blocker losartan. Elevated or decreased functionality of GLUT9 due to polymorphisms was linked to hyper- or hypouricemia, respectively.
GLUT9 is not featured in FDA or EMA guidance.

Localization

GLUT9 displays the typical 12-transmembrane helix structure of the GLUT family [1]. Two splice variants of GLUT9 have been reported which only differ in their cytoplasmic N-terminus [2]. GLUT9a is expressed ubiquitously, mainly in the kidney, liver and placenta, and to a smaller extent in the lungs, brain and leukocytes, while GLUT9b is mainly restricted to the kidney and the placenta [2]. In the human kidney GLUT9a is present in the basolateral membrane of proximal tubule cells, whereas GLUT9b was found in the apical membrane in the collecting ducts [3]. GLUT9 is also present in chondrocytes [4] and was shown to be expressed in the murine gut [5]. Importantly, the localization of GLUT9 may differ between species, e.g. in the murine kidney it can be found mainly in the distal convoluted tubule and in the connecting tubule [6]. In mice, a sizable amount of GLUT9 is present in the plasma membrane of hepatocytes which metabolise uric acid to allantoin. In this context, GLUT9 is believed to facilitate uric acid uptake into hepatocytes [6].

Function, physiology, and clinically significant polymorphisms

GLUT9 is a member of the GLUT family of transport facilitators primarily consisting of monosaccharide and polyol transporters [7]. As such, GLUT9 was believed to be a high-affinity, low-capacity transporter of D-glucose [8,9], deoxyglucose [2] and fructose [9], but the reproducibility of these initial findings was inconsistent and now GLUT9 is widely accepted as a uric acid transporter [10,11,12,13]. The two isoforms of GLUT9, GLUT9a and GLUT9b, differ in their cytoplasmic N-terminus [2] and are identical regarding their urate transport activity [10]. IGF-1 was suggested to regulate GLUT9 expression [14].

GLUT9 is thought to act as a uniporter, but not all other possibilities were refuted [12,15, 1]. In one study GLUT9 was shown to behave as an exchange transporter, exchanging uric acid for glucose and fructose [12], but this mechanism was not confirmed by others. GLUT9 most likely mediates the efflux of urate under the physiological circumstances present in the proximal tubule cells [10]. Uric acid transport by GLUT9 is electrogenic and voltage-dependent [10, 15, 1]. GLUT9a, but not GLUT9b, is also chloride-dependent and can be inhibited by iodide [16].

Uric acid homeostasis is complex and incompletely understood. Uric acid is the product of purine metabolism, so its production depends on both recycling and dietary intake of purine [15]. Approximately two thirds of uric acid clearance takes place in the kidney, while the remaining third is excreted via the enterocytes of the gut [17]. The mechanism of uric acid clearance in enterocytes is not yet fully understood, but GLUT9 has been suggested to play a role as a basolateral transporter in mice [5]. In the human kidney, a large proportion of secreted urate is reabsorbed [16, 18], and GLUT9a was suggested to contribute to uric acid reabsorption by enabling the basolateral efflux of urate taken up from the proximal tubule by luminal transporters such as URAT1 [19]. The role of GLUT9b remains to be clarified.

The significance of elevated serum uric acid levels in humans and higher primates compared to other mammals is a long-standing puzzle in physiology. Unusually high serum urate is caused by the lack of the functional form of the enzyme uricase which degrades uric acid to allantoin in other mammals. As high levels of uric acid in the serum (hyperuricemia) have been linked to gout, hypertension, cardiovascular disease and metabolic syndrome, uric acid has long been seen as a harmful waste product of purine metabolism with no physiological role. More recently, however, this unbalanced view is undergoing revision following the discovery of the strong antioxidant and neuroprotective properties of uric acid [20,21,22,23] and the elucidation of its role in the recognition of dying cells by the immune system [24,25]. These novel results suggest an important and complex physiological role for uric acid in redox balance, neuroprotection, and tissue homeostasis.

Several polymorphisms of GLUT9 were shown to have a strong connection with serum urate levels. Patients with mutations of GLUT9 which do not support uric acid transport have shown signs of hypouricemia or a reduced prevalence of hyperuricemia [10, 13,18,26,27]. Genome-wide studies have revealed association of some GLUT9 SNPs with elevated levels of uric acid in the blood and gout [13,28].

Clinical significance

Hyperuricemia (high level of uric acid in the blood) has been linked to gout, hypertension, cardiovascular disease and metabolic syndrome. Medical treatment of these illnesses typically targets URAT1, one of the transporters responsible for the reabsorption of uric acid from the primary filtrate to blood through proximal tubule cells. Although no drugs have been designed to directly target GLUT9, the uricosuric drugs benzbromarone [10,12,15] and probenecid [10] were able to inhibit urate uptake by GLUT9. The angiotensin II receptor blocker losartan was shown to be an inhibitor of GLUT9 as well [10,15]. Phloretin, a glucose-transporter blocker inhibited murine, but not human, GLUT9 [12,15]. Currently there are no known drug substrates of GLUT9.

Regulatory requirements

The current FDA and EMA guidelines contain no recommendation on testing NCEs for interactions with GLUT9.

Table: Summary information for GLUT9

Localization

Endogenous substrates

In vitro substrates used experimentally

Substrate drugs

Inhibitors

GLUT9a: ubiquitous

GLUT9b: kidney, placenta

Uric acid

Uric acid

None identified

Losartan

Benzbromarone

 

References:

1: Clémençon, B., et al., Expression, Purification, and Structural Insights for the Human Uric Acid Transporter, GLUT9, Using the Xenopus laevis Oocytes System PLoS One. 2014; 9(10): e108852.

2: Augustin, R., et al., Identification and Characterization of Human Glucose Transporter-like Protein-9 (GLUT9) J Biol Chem. 2004 Apr 16;279(16):16229-36.

3: Kimura, T., et al., Expression of SLC2A9 Isoforms in the Kidney and Their Localization in Polarized Epithelial Cells PLoS One. 2014 Jan 7;9(1):e84996.

4: Mobasheri, A., et al., Human articular chondrocytes express three facilitative glucose transporter isoforms: GLUT1, GLUT3 and GLUT9. Cell Biol Int. 2002;26(3):297-300.

5: DeBosch, B., J., et al., Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9 Nat Commun. 2014 Aug 7;5:4642.

6: Preitner, F., et al., Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy Proc Natl Acad Sci U S A. 2009 Sep 8; 106(36): 15501–15506.

7: Mueckler, M., and Thorens, B., The SLC2 (GLUT) Family of Membrane Transporters Mol Aspects Med. 2013 ; 34(0): 121–138.

8: Doege, H., et al., 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 Biochem. J. 2000, 350, 771–776

9: Manulescu, A., R., et al., A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity Mol Membr Biol. 2007 Sep-Dec;24(5-6):455-63.

10: N., Anzai, et al., Plasma Urate Level Is Directly Regulated by a Voltage-driven Urate Efflux Transporter URATv1 (SLC2A9) in Humans J Biol Chem. 2008 Oct 3;283(40):26834-8.

11: Ebert, K., et al., Reassessment of GLUT7 and GLUT9 as Putative Fructose and Glucose Transporters J Membr Biol. 2017 Apr;250(2):171-182.

12: Caulfield, M., J., et al., SLC2A9 Is a High-Capacity Urate Transporter in Humans PLoS Med. 2008 Oct; 5(10): e197.

13: Vitart, V., et al., SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout Nat Genet. 2008 Apr;40(4):437-42.

14: Mannino, G., C., et al., The polymorphism rs35767 at IGF1 locus is associated with serum urate levels Sci Rep. 2018; 8: 12255.

15: Bibert, S., et al., Mouse GLUT9: evidences for a urate uniporter Am J Physiol Renal Physiol. 2009 Sep;297(3):F612-9.

16: Lüscher, B., P., et al., Different Pharmacological Properties of GLUT9a and GLUT9b: Potential Implications in Preeclampsia Cell Physiol Biochem 2019;53:508-517

17: Pascual, E. and Perdiguero, M., Gout, diuretics and the kidney Ann Rheum Dis. 2006 Aug; 65(8): 981–982.

18: Ruiz, A., et al., Human Mutations in SLC2A9 (Glut9) Affect Transport Capacity for Urate Front Physiol. 2018 Jun 18;9:476.

19: So, A. and Thorens, B., Uric acid transport and disease J Clin Invest. 2010 Jun 1; 120(6): 1791–1799.

20: M., Bi, et al., Glut9-mediated Urate Uptake Is Responsible for Its Protective Effects on Dopaminergic Neurons in Parkinson’s Disease Models, Front Mol Neurosci. 2018; 11: 21.

21: Schwarzschild, M., A., et al., Serum urate as a predictor of clinical and radiographic progression in Parkinson’s disease Arch Neurol. 2008 Jun; 65(6): 716–723.

22: Ascherio, A., et al., Urate predicts rate of clinical decline in Parkinson disease Arch Neurol. 2009 Dec; 66(12): 1460–1468.

23: Mandal, A., K., and Mount, D., B. Interaction Between ITM2B and GLUT9 Links Urate Transport to Neurodegenerative Disorders Front Physiol. 2019 Oct 22;10:1323.

24: Shi, Y., Evans, J., E., and Rock, K., L., Molecular identification of a danger signal that alerts the immune system to dying cells Nature. 2003 Oct 2;425(6957):516-21.

25: Martinon, F., et al., Gout-associated uric acid crystals activate the NALP3 inflammasome Nature 2006 volume 440, pages237–241

26: S., Li, et al., The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts PLoS Genet. 2007 Nov; 3(11): e194.

27: H., Matsuo, et al., Mutations in Glucose Transporter 9 Gene SLC2A9 Cause Renal Hypouricemia Am J Hum Genet. 2008 Dec 12; 83(6): 744–751.

28: Döring, A., et al., SLC2A9 influences uric acid concentrations with pronounced sex-specific effects Nat Genet. 2008 Apr ;40, pages 430–436

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