SGLT5

SGLT5  and SGLT4 (sodium-glucose linked transporter 5 and 4 or sodium/glucose cotransporter 5 and 4)

Aliases: None

Gene names: Solute carrier family 5 member 9 (SLC5A9); Solute carrier family 5 member 10 (SLC5A10)

Summary

Most monosaccharides, including fructose, glucose, galactose, mannose, as well as myo-inositol are transported across the cell membrane by either of two types of glucose transporters: facilitated glucose transporters (GLUTs) and sodium/glucose cotransporters (SGLTs). SGLT4, a member of the solute carrier family SLC5 [1], is a low affinity-type sodium/glucose cotransporter. SGLT4 is suspected to transport mannose, fructose and 1,5-anhydroglucitol (1,5-AG) in the kidney. SGLT5 is also a member of the solute carrier family SLC5. It is a characterized kidney mannose transporter, with probably more physiological roles unexplored.

Localization

SGLT4 was found by immunolocalization in the luminal membrane of intestinal epithelial cells [2]. It is expressed at comparatively high levels in the small intestine and kidney, with moderate expression detected in the liver. SGLT5 is highly expressed in the kidney but absent from all other tissues [3, 4]. Both SGLT4 and SGLT5 were found to be localized to the luminal (apical) but not the basolateral membrane of proximal tubule cells in the S2 segment [2]. 

Function, physiology, and clinically significant polymorphisms

SGLT4 is a 74,073 Da membrane protein with 14 transmembrane helices [1]. It is believed to take part in the transport of D-mannose, D-glucose and D-fructose in the small intestine [5]. In hSGLT4-expressing cells, the apparent K_m and Vm_ax values for methyl-α-D-glucopyranoside (AMG) were 2.6 mM and 29 pmol/well/min, respectively. This apparent Km value suggests that hSGLT4 belongs to the low-affinity hexose transporters [5].
SGLT5 is a 64,342 Da membrane protein with 14 transmembrane helices [1]. In [14C]-AMG uptake experiments performed using a range of concentrations of mannose, fructose, glucose and galactose, all monosaccharides were shown to compete with [14C]-AMG, with mannose and fructose exhibiting the greatest competitive activity: IC50 values were 1.1 mM for mannose and 2.2 mM for fructose. Competition by glucose and galactose was also observed, although at higher IC₅₀ values (5.2 mM and 8.0 mM, respectively). These results indicate that SGLT5 has an affinity for these monosaccharides with a rank order of mannose > fructose > glucose > galactose [3]. Remogliflozin inhibited SGLT5 with mean Ki values of 83 nM (fructose uptake), 170 nM (mannose uptake) and 480 nM (AMG uptake), indicating a selectivity window of 7- to 40-fold versus SGLT2 [3]. 
In a 2018 study, an intronic variant of the SLC5A10 gene affected not SGLT5 but DRG2 expression, resulting in worse overall and disease-free survival of non-small-cell lung cancer patients [6].

Clinical significance

SGLT4 is a promising therapeutic target in patients with invasive candidiasis [7], diabetes mellitus [8] and metabolic syndrome [9], as these diseases are linked with the elevation of serum mannose concentration, and SGLT4 is a main candidate for the transporter-mediated reabsorption of mannose in the kidney [10].
Although the renal/intestinal transporter for 1,5-AG has not yet been identified, the substrate specificity and mRNA distribution of SGLT4 make it a good candidate for the role. If confirmed, SGLT4 may emerge as an important transporter in the control of the serum concentrations of 1,5-AG both in the kidneys and in the small intestine, and a potential therapeutic target [5].
The widespread use of high-fructose corn syrup in food industry has led to increased dietary fructose consumption in some populations. In the kidney, renal proximal tubules are thought to reabsorb fructose; however, fructose reabsorption by proximal tubules has never been demonstrated directly. Proximal tubule epithelial cells express sodium-glucose linked transporters (SGLTs) 1, 2, 4 and 5, and glucose transporters (GLUTs) 2 and 5. SGLT4 and 5 transport fructose but SGLT1 and 2 do not [2]. In a recent study, it was concluded that an increase in fructose consumption results in enhanced SGLT4, SGLT5 and GLUT2 expression and elevated plasma fructose concentrations [2].
It was proven that 65-85% of fructose reabsorption in the S2 segment of renal proximal tubules can be inhibited by either removal of Na⁺ from the perfusate or by phlorizin, an SGLT blocker. Furthermore, in the S2 segment research has found no evidence of apical expression of either GLUT2 or GLUT5, the only GLUTs known to be expressed in proximal tubules. As there is no passive mechanism to facilitate the movement of fructose across the membrane of S2 proximal tubule cells, fructose reabsorption is presumably mediated by either SGLT4 or SGLT5 [2]. Both transporters were compared with regard to kinetic properties of fructose uptake in overexpressing HEK293 cells, and SGLT5 displayed much higher affinity to fructose. Therefore, SGLT5 is speculated to be the major contributor to fructose reabsorption in the kidney [4, 11]. 

Regulatory requirements

Glucose transporters are not significantly involved in DDI or drug ADME; therefore, the FDA or EMA guidances contain no recommendations on their in vitro investigation.

Table: Summary information for SGLT5

References

1.    Wright, E.M. and E. Turk, The sodium/glucose cotransport family SLC5. Pflugers Archiv European Journal of Physiology, 2004. 447(5): p. 510-518.
2.    Gonzalez-Vicente, A., et al., Fructose reabsorption by rat proximal tubules: role of Na + -linked cotransporters and the effect of dietary fructose. American journal of physiology. Renal physiology, 2019. 316(3): p. F473-F480.
3.    Grempler, R., et al., Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter. FEBS Letters, 2012. 586(3): p. 248-253.
4.    Fukuzawa, T., et al., SGLT5 Reabsorbs Fructose in the Kidney but Its Deficiency Paradoxically Exacerbates Hepatic Steatosis Induced by Fructose. PLoS ONE, 2013. 8(2): p. 1-11.
5.    Tazawa, S., et al., SLC5A9/SGLT4, a new Na +-dependent glucose transporter, is an essential transporter for mannose, 1,5-anhydro-D-glucitol, and fructose. Life Sciences, 2005. 76(9): p. 1039-1050.
6.    Hong, M.J., et al., Functional intronic variant of SLC5A10 affects DRG2 expression and survival outcomes of early-stage non-small-cell lung cancer. Cancer Science, 2018. 109(12): p. 3902-3909.
7.    Monson, T.P. and K.P. Wilkinson, Mannose in body fluids as an indicator of invasive candidiasis. Journal of Clinical Microbiology, 1981. 14(5): p. 557-562.
8.    Pitkänen, E., Mannose, mannitol, fructose and 1,5-anhydroglucitol concentrations measured by gas chromatography/mass spectrometry in blood plasma of diabetic patients. Clinica Chimica Acta, 1996. 251(1): p. 91-103.
9.    Pitkänen, O.M., H. Vanhanen, and E. Pitkänen, Metabolic syndrome is associated with changes in D-mannose metabolism. Scandinavian Journal of Clinical and Laboratory Investigation, 1999. 59(8): p. 607-612.
10.    Mendelssohn, D.C. and M. Silverman, A D-mannose transport system in renal brush-border membranes. American Journal of Physiology-Renal Physiology, 1989. 257(6): p. F1100-F1107.
11.    Ghezzi, C., et al., Fingerprints of hSGLT5 sugar and cation selectivity. American Journal of Physiology - Cell Physiology, 2014. 306(9): p. 864-870.