The human tumour suppressor gene SLC5A8 expresses a Na⁺–monocarboxylate cotransporter

Abstract

The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na + and was compatible with a 3 : 1 stoichiometry between Na + and monocarboxylates. A portion of the SMCT-mediated current was also Cl − dependent, but Cl − was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated K m values near 100 µM, apart from acetate and D-lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mM probenecid or ibuprofen. In the absence of external substrate, a Na + -independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na + , short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na + -monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti-proliferative and apoptosis-inducing activity in colon epithelial cells.

Histochemical demonstration of a Na+-coupled transporter for short-chain fatty acids (Slc5a8) in the intestine and kidney of the mouse

“…For immunohistochemistry, deeply anesthetized animals were perfused via the aorta with physiological saline, followed by 4% paraformaldehyde in 0.1 M phosphate buffer (PB) (pH 7.4). The tissues menacid (the 1-carbon SCFA) and acetic acid (the 2-carbon SCFA) than upon that of larger SCFAs (6). In that study, L-lactate and pyruvate also induced large currents through Slc5a8 (6).…”

“…The tissues menacid (the 1-carbon SCFA) and acetic acid (the 2-carbon SCFA) than upon that of larger SCFAs (6). In that study, L-lactate and pyruvate also induced large currents through Slc5a8 (6). Early studies have demonstrated the existence of a Na + -coupled lactate transport system in the brush border membrane of the kidney (2,3).…”

“…It has also been shown that SCFAs prevent colonic cell proliferation and reduce the incidence of colon cancer (4,5,21). Slc5A8, a tumor suppressor gene down-regulated in colon cancer, codes for a Na + -coupled transporter for SCFAs and other monocarboxylates such as lactate and pyruvate (6,9,15). Transfection of the Slc5a8 gene into Xenopus laevis oocytes increased the uptake of these monocarboxylates Na + -dependently, the rates of increase being especially high for lactate, pyruvate, and propionate (15).…”

Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8

“…More recently, a potent membrane transporter for SCFA, namely solute-linked carrier 5a8 (slc5a8), was identifi ed as a Na + -coupled co-transporter for SCFA and lactate (5,12,20). In contrast to MCT, which functions as H + -coupled electroneutral transporters, slc5a8 functions as a Na + -coupled electrogenic transporter.…”

Olfaction in the kidney: ‘smelling’ gut microbial metabolites

“…Short‐chain fatty acids produced in the colon are then taken up into the circulation by monocarboxylate transporters (Coady et al . 2004) and by free diffusion. Thus, although changes in host metabolism or in dietary intake may additionally modulate serum SCFA concentrations, it is clear that gut microbial production is a major determinant of circulating SCFAs.…”