Human Transporters

SGLT5New

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

Aliases: None

Gene names: 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). SGLT5 is a member of the solute carrier family SLC5. It is a characterized kidney mannose transporter, with probably more physiological roles unexplored.

Localization

SGLT5 is highly expressed in the kidney but absent from all other tissues [4], [5]. B SGLT5 was 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

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 [4]. 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 [4].

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 [3].

Clinical significance

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 [5], [6].

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

Location Endogenous substrates In vitro substrates used experimentally

Substrate drugs

Inhibitors
kidney D-mannose, D-glucose, D-fructose and galactose AMG, fructose, mannose - phlorizin, gliflozins

 

References

[1]        E. M. Wright and E. Turk, “The sodium/glucose cotransport family SLC5,” Pflugers Arch. Eur. J. Physiol., vol. 447, no. 5, pp. 510–518, 2004, doi: 10.1007/s00424-003-1063-6.

[2]        A. Gonzalez-Vicente, P. D. Cabral, N. J. Hong, J. Asirwatham, F. Saez, and J. L. Garvin, “Fructose reabsorption by rat proximal tubules: role of Na + -linked cotransporters and the effect of dietary fructose,” Am. J. Physiol. Renal Physiol., vol. 316, no. 3, pp. F473–F480, Mar. 2019, doi: 10.1152/ajprenal.00247.2018.

[3]        M. J. Hong et al., “Functional intronic variant of SLC5A10 affects DRG2 expression and survival outcomes of early-stage non-small-cell lung cancer,” Cancer Sci., vol. 109, no. 12, pp. 3902–3909, 2018, doi: 10.1111/cas.13814.

[4]        R. Grempler et al., “Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter,” FEBS Lett., vol. 586, no. 3, pp. 248–253, 2012, doi: 10.1016/j.febslet.2011.12.027.

[5]        T. Fukuzawa et al., “SGLT5 Reabsorbs Fructose in the Kidney but Its Deficiency Paradoxically Exacerbates Hepatic Steatosis Induced by Fructose,” PLoS One, vol. 8, no. 2, pp. 1–11, 2013, doi: 10.1371/journal.pone.0056681.

[6]      C. Ghezzi et al., “Fingerprints of hSGLT5 sugar and cation selectivity,” Am. J. Physiol. - Cell Physiol., vol. 306, no. 9, pp. 864–870, 2014, doi: 10.1152/ajpcell.00027.2014.

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