Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Cell Physiol
2016 Nov 01;3115:C720-C734. doi: 10.1152/ajpcell.00104.2015.
Show Gene links
Show Anatomy links
Insulin and SGK1 reduce the function of Na+/monocarboxylate transporter 1 (SMCT1/SLC5A8).
López-Barradas A
,
González-Cid T
,
Vázquez N
,
Gavi-Maza M
,
Reyes-Camacho A
,
Velázquez-Villegas LA
,
Ramírez V
,
Zandi-Nejad K
,
Mount DB
,
Torres N
,
Tovar AR
,
Romero MF
,
Gamba G
,
Plata C
.
???displayArticle.abstract???
SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.
Ahmed,
GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors.
2009, Pubmed
Ahmed,
GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors.
2009,
Pubmed
Ahmed,
Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis.
2009,
Pubmed
Arroyo,
Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway.
2011,
Pubmed
,
Xenbase
Borthakur,
The probiotic Lactobacillus plantarum counteracts TNF-{alpha}-induced downregulation of SMCT1 expression and function.
2010,
Pubmed
Boyd,
Gene regulation of ENaC subunits by serum- and glucocorticoid-inducible kinase-1.
2005,
Pubmed
Brown,
The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.
2003,
Pubmed
,
Xenbase
Cline,
Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis.
2011,
Pubmed
Coady,
The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.
2004,
Pubmed
,
Xenbase
Dieter,
Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB.
2004,
Pubmed
,
Xenbase
Frank,
Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice.
2008,
Pubmed
Frayling,
A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.
2003,
Pubmed
Gao,
Distinguishing features of leucine and alpha-ketoisocaproate sensing in pancreatic beta-cells.
2003,
Pubmed
Gopal,
Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney.
2007,
Pubmed
,
Xenbase
Halestrap,
The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond.
2004,
Pubmed
Halestrap,
The monocarboxylate transporter family--role and regulation.
2012,
Pubmed
Halestrap,
The monocarboxylate transporter family--Structure and functional characterization.
2012,
Pubmed
Hallows,
Phosphopeptide screen uncovers novel phosphorylation sites of Nedd4-2 that potentiate its inhibition of the epithelial Na+ channel.
2010,
Pubmed
,
Xenbase
Hellman,
The mechanisms of action of chloromercuribenzene-p-sulphonic acid as insulin secretagogue: fluxes of calcium, sodium and rubidium in islets exposed to mercurial and a membrane-active antagonist.
1975,
Pubmed
Helm,
SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma.
2012,
Pubmed
Helms,
Hormone-regulated transepithelial Na+ transport in mammalian CCD cells requires SGK1 expression.
2003,
Pubmed
Hong,
Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8.
2005,
Pubmed
Ishihara,
Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells.
1999,
Pubmed
Itagaki,
Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8).
2006,
Pubmed
,
Xenbase
Iwanaga,
Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8.
2006,
Pubmed
Jiang,
[The methylation and mRNA expression of SLC5A8 and TMS1/ASC genes in human glioma].
2007,
Pubmed
Jitrapakdee,
Regulation of insulin secretion: role of mitochondrial signalling.
2010,
Pubmed
Kobayashi,
Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.
1999,
Pubmed
Lang,
Targeting SGK1 in diabetes.
2009,
Pubmed
Lang,
(Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms.
2006,
Pubmed
Lang,
Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1.
2013,
Pubmed
Li,
SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers.
2003,
Pubmed
Li,
Regulation of leucine-stimulated insulin secretion and glutamine metabolism in isolated rat islets.
2003,
Pubmed
Lin,
Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness.
2011,
Pubmed
Lindgren,
Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study.
2002,
Pubmed
López,
Characterization and regulation of the gene expression of amino acid transport system A (SNAT2) in rat mammary gland.
2006,
Pubmed
MacDonald,
Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion.
2005,
Pubmed
Martin,
Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.
2006,
Pubmed
,
Xenbase
Miyauchi,
Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids.
2004,
Pubmed
,
Xenbase
Naoumova,
Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia.
2003,
Pubmed
Noriega-López,
Pancreatic insulin secretion in rats fed a soy protein high fat diet depends on the interaction between the amino acid pattern and isoflavones.
2007,
Pubmed
Otonkoski,
Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells.
2007,
Pubmed
Palmada,
SGK1 kinase upregulates GLUT1 activity and plasma membrane expression.
2006,
Pubmed
,
Xenbase
Park,
Gene silencing of SLC5A8 identified by genome-wide methylation profiling in lung cancer.
2013,
Pubmed
Park,
Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.
2008,
Pubmed
Park,
Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor.
2007,
Pubmed
Paroder,
Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT.
2006,
Pubmed
,
Xenbase
Pérusse,
A genome-wide scan for abdominal fat assessed by computed tomography in the Québec Family Study.
2001,
Pubmed
Plata,
Zebrafish Slc5a12 encodes an electroneutral sodium monocarboxylate transporter (SMCTn). A comparison with the electrogenic SMCT (SMCTe/Slc5a8).
2007,
Pubmed
,
Xenbase
Poole,
Transport of lactate and other monocarboxylates across mammalian plasma membranes.
1993,
Pubmed
Porra,
Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.
2005,
Pubmed
Pullen,
Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise.
2012,
Pubmed
Shojaiefard,
Regulation of the Na(+), glucose cotransporter by PIKfyve and the serum and glucocorticoid inducible kinase SGK1.
2007,
Pubmed
,
Xenbase
Shoulders,
Genetics of familial combined hyperlipidemia and risk of coronary heart disease.
2004,
Pubmed
Smith,
Effects of monensin on metabolism of isolated rat islets of Langerhans.
1984,
Pubmed
Srinivas,
Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2).
2005,
Pubmed
,
Xenbase
Stoddart,
International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions.
2008,
Pubmed
Takebe,
Histochemical demonstration of a Na(+)-coupled transporter for short-chain fatty acids (slc5a8) in the intestine and kidney of the mouse.
2005,
Pubmed
Thangaraju,
c/ebpdelta Null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney.
2006,
Pubmed
Thangaraju,
Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.
2009,
Pubmed
,
Xenbase
Thangaraju,
Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3.
2009,
Pubmed
Ueno,
Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer.
2004,
Pubmed
Waldegger,
Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume.
1997,
Pubmed
Whitman,
DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication.
2008,
Pubmed
Xing,
Gene methylation in thyroid tumorigenesis.
2007,
Pubmed
Zhang,
Activin A induces SLC5A8 expression through the Smad3 signaling pathway in human colon cancer RKO cells.
2010,
Pubmed
Zhao,
Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas.
2001,
Pubmed
