They transport sodium cations in association with the anionic forms (see conjugated base) of certain short-chain fatty acids (i.e., SC-FAs) through the plasma membrane from the outside to the inside of cells.
SMCT1-expressing cells in the kidney[16] and salivary glands[15] retrieve the SC-FAs in the urine and saliva, respectively, which otherwise would be wastefully discarded.
Furthermore, the SC-FAs that enter cells can activate signal transduction pathways which elicit cellular responses independently of the three cited SC-FA receptors.
[18] It may also underlie the apparent ability of high SMCT1 levels to suppress the development and/or progression of breast, pancreas, lung, brain, thyroid, stomach, prostate, and head & neck cancers.
However, these anti-cancerous effects are based primarily on studies finding that, compared to the normal cells in the tissues of these cancers, the cancer cells expressed lower levels of the messenger RNA (i.e., mRNA) that directs formation of the SMCT1 protein.
[27] As indicated in the cancer studies described below, humans, mice, rats, and/or rabbits express SMCT1 mRNA and/or protein in their normal breast, pancreas, lung, brain, thyroid, stomach, prostate, and certain head & neck tissues.
[28] This transfer is an electrogenic cotransporter process in which at least two Na+ cations and one carboxylate-containing anionic compound pass into a cell.
[11] (Hereafter, the acid names of the agents transported by SMCT1 will be used with the understanding that it is their anionic forms which actually enter cells.)
Bacteria in the gastrointestinal tract generate and release various SC-FAs, e.g., butyric, propionic, lactic, acetic,[5] and β-hydroxybutyric acids.
[29] The SC-FAs released by these bacteria as well as those in the host's diet diffuse into the intestine's wall where they are transported into cells that express SMCT1.
This study also showed that mice lacking SMCT1 due to the knockout of their Slc8a5 gene had massive increases in the levels of lactic acid in their urine.
This study indicates that SMCT1 protein is essential for the kidney to absorb lactic acid and presumably other SC-FAs from the urine in mice.
[15] The absorption of SC-FAs from the urine is suggested to be an alternative energy source for the kidney cells especially during times of stress.
These findings indicate that the SMCT1 in salivary gland cells mediates the reabsorption of the lactic acid and probably other SC-FAs from the saliva in mice.
The function of SMCT1 in the skeletal muscle cells of mice has not been studied but is suggested to have a role in their handling of lactic acid.
Resting skeletal muscle cells actively take up lactic acid and use it as an energy source.
[25] In a murine model of dextran sulfate sodium-induced inflammatory colitis, Slc5a8 gene knockout and control mice were feed a diet that reduced the levels of SC-FAs in their intestines.
[23] A recent study reviewed the published controlled trials that used probiotics (which raise the intestinal levels of SC-FAs) to treat ulcerative colitis.
The magnitudes of these responses were similar to those achieved by a drug commonly used to treat ulcerative colitis, 5‐aminosalicylic acid.
The panel concluded that patients with mildly active Krohn's disease who took a probiotic along with their usual anti-colitis medication(s) had an increased rate of remission.
The loss of SMCT1 mRNA expression in human colon cancer tissues and selected cell lines was closely associated with hypermethylation of the CpG sites in exon 1 of the SMCT1 gene; this location contains the putative area that initiates this gene's transcription to form SMCT1 mRNA and protein.
[5][19][37] In a study of 113 patients diagnosed with Dukes classification stage C (i.e., locally advanced lymph node-positive but no distant metastases) colon cancer, survival times were significantly longer in patients with tumors that expressed higher levels of SMCT protein (presumed to be SMCT1 protein).
The study concluded that SMCT1 protein acts to suppress the cited types of human breast cancers.
Treatment of these three cell lines with an inhibitor of CpG site methylation, 5-aza-2′-deoxycytidine (also termed decitabine), increased their levels of SMCT1 mRNA.
The study concluded that SMCT1 protein acts to suppress the development and/or progression of human pancreatic cancers.
[45] Another study found that patients with adenocarcinomas of the lung stages I or II (i.e., cancers localized to a small or larger, respectively, part of the lung) who exhibited high methylation levels in the CpG sites of their SLC5A8 gene had shorter disease-free survival times than patients who did not have this methylation pattern.
2) The human glioma LN229 and LN443 cell lines expressed little or no SMCT1 mRNA, had CpG site hypermethylations similar to that in colon cancer, increased their expression of SMCT1 mRNA when treated with the inhibitor of CpG site methylation, 5-aza-2′-deoxycytidine, and after transfection with a SLC5A8 gene-containing retrovirus vector formed far fewer colonies than LN229 and LN443 cells transfected with an empty viral vector as judged in a laboratory assay that measured the ability of single cells to grow into colonies.
)[48] The two studies concluded that SMCT1 protein acts to inhibit the development and/or progression of human papillary thyroid carcinomas.
The undetectable or reduced levels of SMCT1 were associated with hypermethylations of CpG sites similar to that in colon cancer.
The study concluded that SMCT1 protein acted to suppress the development and/or progression of human prostate cancers.