Sodium-coupled monocarboxylate transporter 1 (i.e., SMCT1) and sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2) are plasma membrane transport proteins in the solute carrier family. 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. For example, propionic acid (i.e., ) in its anionic "propionate" form (i.e., ) along with sodium cations (i.e., Na+) are co-transported from the extracellular fluid into a SMCT1-epxressing cell's cytoplasm. Monocarboxylate transporters (MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with proton cations (i.e. H+). Four of the 14 MCTs, i.e. SLC16A1 (i.e., MCT1), SLC16A7 (i.e., MCT22), SLC16A8 (i.e., MCT3), and SLC16A3 (i.e., MCT4), transport some of the same SC-FAs anions that the SMCTs transport into cells. SC-FAs do diffuse into cells independently of transport proteins but at the levels normally occurring in tissues far greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.
The human SMCT1 and SMCT2 proteins are commonly referred to by the names of the genes responsible for their production, i.e., SLC5A8 and SLC5A12, respectively. The human gene for SMCT1, i.e., the SLC5A8 gene, is located at position 23.1 on the "q" (i.e., long) arm of chromosome 12 (notated as 12q23); SMCT2's gene, i.e., the SLC5A12 gene, is located at position 14.2 on the "p" (i.e., short) arm of chromosome 11 (notated as chromosome 11p14.2) The SMCT1 and SMCT2 proteins consist of 618(https://www.uniprot.org/uniprotkb/Q8N695/entry) and 618 amino acids, respectively, and have 57% identity at the amino acid level. (The animal proteins are, like the human proteins, here termed SMCT1 and SMCT2 while their genes are termed Slc8a5 and Slc5a12, respectively.) Compared to SMCT1, there have been far fewer reported studies on SMCT2.
SC-FAs come from two sources: the diet and, perhaps more importantly, their release from intestinal bacteria. The intestinal SC-FAs diffuse into the intestine/s wall, enter SMCT1-bearing cells, and diffuse into the blood. These SA-FAs serve as energy sources for cells located in the intestinal wall and throughout the body. The absorbed SC-FAs also stimulate various functions in cells throughout the body that express one of the SC-FA receptors, i.e., free fatty acid receptor 2, free fatty acid receptor 3, or hydroxycarboxylic acid receptor 2. (For the functions elicited by SC-FA's activation of these receptors see free fatty acid receptor 2 functions, free fatty acid receptor 3 functions, and hydroxycarboxylic acid receptor 2 functions.) SMCT1 thereby functions to take up intestinal SC-FAs that have nutritional and wide-ranging stimulating effects. SMCT1 has other functions. SMCT1-expressing cells in the kidney and salivary glands 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. This appears to the mechanism underlying the ability of high SMCT1 levels in kidney cells to ameliorate diabetic kidney disease. 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. Most of these studies did not measure the levels of SMCT1 protein but rather inferred their levels based on their SMCT1 mRNA levels. Studies have shown that the relation between the level of a mRNA and its protein can vary greatly, i.e., that SMCT1 mRNA levels are not always good indicators of SMCT1 protein levels. This and discrepant findings in studies on colon and pancreas cancers indicate that the role of SMCT1 protein in these cancers requires further investigations.
Cells and tissues expressing SMCT1 The cells and tissues that express SMCT1 mRNA and/or protein include: enterocytes (i.e., simple columnar epithelial cells) in the ilium and colon of humans, mice, and rats; skeletal muscle of mice; kidney brush border cells in the S2 and S3 sections of the straight proximal tubules and cells in the medulla of mice, rats, rabbits, and humans; cells in the salivary glands of mice; neurons in various areas of mouse and rat brains and the astrocytes in rat brains; and cells in the ganglion cell layer, inner nuclear layer, inner plexiform layer, outer plexiform layer, photoreceptor inner segments, and retinal pigment epithelium in the eyes of mice. 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.
Agents transported by or blocking SMCT1 The SC-FAs that SMCT1 transfers into cells include the anionic forms of butyric, proprionic, lactic, acetic, pyruvic acid, and β-hydroxybutyric acids. SMCT1 also transfers the anionic forms of nicotinic acid, the cyclic amino acid pyroglutamic acid, benzoic acid, and pharmacological and therapeutic drugs such as dichloroacetic acid, bromopyruvic acid, Mesalazine (also termed 5-aminosalicylic acid), salicylic acid, and β-hydroxy β-methylbutyric acid. This transfer is an electrogenic cotransporter process in which at least two Na+ cations and one carboxylate-containing anionic compound pass into a cell. SMCT2 similarly transfers the cited SC-FAs acids into cells but its affinity for them is less than SMCT1's. Nonsteroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen bind to but are not transported by SMCT1. However, their binding blocks the binding and thereby transportation of the anionic SC-FAs and, presumably, the other anionic compounds that SMTC1 normally transports into cells. (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.)
Functions of SMCT1 Gastrointestinal tract Bacteria in the gastrointestinal tract generate and release various SC-FAs, e.g., butyric, propionic, lactic, acetic, and β-hydroxybutyric acids. 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. The SMCT1-expressing cells are located in the intestinal epithelium from the distal end of the small intestine down to the distal end of the colon. Studies in rodents and humans indicate that the transported SC-FAs: 1) are metabolized for energy by the endothelial cells and stimulate certain white blood cells) in the intestinal walls; 2) diffuse into the portal vein system and enter liver cells which use them for energy or convert them to longer-chain fatty acids for storage; and 3) pass from the liver to the systemic circulation where they serve as energy for and regulate a wide range of functions in cells that express one of the three SC-FA receptors described above.
Kidney In one study, SMTC1 mRNA was detected in the kidney cortex's proximal tubules and medulla of mice and in the kidney brush border of rabbits. Vesicles isolated from the kidney's brush borders of rabbits actively incorporated lactic acid and based on indirect studies other SC-FAs, e.g., acetic, propionic, and butyric acids. A second study detected SMTC1 protein as well as mRNA in the kidney cortex, tubules, and medulla of mice. 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. 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. However, the Slc8a5 gene knockout study in mice did not detect any kidney damage.
In further studies, SMTC1 protein was detected in the brush borders of the proximal convoluted tubules in kidney biopsy specimens taken from patients with diabetic kidney disease; the level of SMCT1 protein in the kidney biopsies of these patients was 78.6% lower than that in the biopsies of the normal renal tissues from patients with kidney cancer (this cancer was considered to be incidental to the analysis). The study also found that in a murine model of streptozotocin-induced type 2 diabetes and associated diabetic kidney disease: 1) type 2 diabetic mice (i.e. T2D mice) had lower kidney levels of SMCT1 mRNA than control mice; 2) T2D mice that had the Slc5a8 gene in their renal tubules knocked out and therefore lacking SMCT1 protein developed far more severe kidney disease than T2D mice that did not have this gene knocked out; 3) T2D mice transfected with an adeno-associated viral vector containing the Slc5a gene expressed higher levels of SMCT1 and showed marked improvements in their kidney disease; 4) T2D mice treated with oral 1,3-butanediol (which the liver converts to β-hydroxybutyric acid) showed less damaged kidneys than untreated mice; and 5) a study of 100 patients with diabetes found that the higher their blood serum acetic acid or butyric acid levels were the less likely they were to have diabetes-associated kidney disease. These findings indicate that lower kidney SMTC1 levels are associated with more severely damaged kidneys in mice and humans with T2D diabetes; 1,3-butanediol, which is converted to the SC-FA, β-hydroxybutyric acid, ameliorated diabetes-associated kidney disease in mice; and diabetic humans with higher serum levels of acetic or butyric acid were less likely to have diabetes-associated kidney disease. The study suggested that future studies should be conducted to determine if treating diabetic humans with SC-FAs reduces their chances of developing and/or is an effective treatment for the kidney damage associated with diabetes.
Salivary glands A study showed that SMTC1 protein is expressed by cells in the intercalated ducts and acini of the parotid and the acini of the submandibular salivary glands of mice. Compared to normal mice, Slc5a8 gene knockout mice had significantly higher levels of lactic acid in their saliva when evaluated with a pilocarpine-induced salivation test. 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. This relationship appears similar to that found for the kidney's uptake of urinary SC-FAs.
Skeletal muscle 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. SMCT1 may contribute to the delivery of this energy source to these cells.
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