Identification of a mutation in the ileal sodium-dependent bile acid transporter gene that abolishes transport activity.
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The ileal Na+/bile acid cotransporter mediates reabsorption of bile acids from the small intestine.
"The ileal Na+/bile acid cotransporter plays a critical role in the reabsorption of bile acids from the small intestine."
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The P290S substitution abolishes taurocholate transport without altering synthesis or subcellular distribution of the transporter, separating catalytic competence from trafficking.
"In transfected COS-1 cells, the single amino acid change abolished taurocholate transport activity but did not alter the transporter's synthesis or subcellular distribution."
Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2).
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SLC10A2 mutations cause primary bile acid malabsorption, establishing the gene's role in intestinal reclamation of bile acids.
"These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile acids."
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The L243P and T262M disease alleles traffic normally to the plasma membrane but abolish transport of taurocholate and other bile acids.
"In transfected COS cells, the L243P, T262M, and double mutant (L243P/T262M) did not affect transporter protein expression or trafficking to the plasma membrane; however, transport of taurocholate and other bile acids was abolished."
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The clinical phenotype of SLC10A2 deficiency is interruption of the enterohepatic circulation of bile acids with diarrhea, steatorrhea and low plasma cholesterol.
"Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels."
Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter.
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Human ileal transporter-mediated taurocholate uptake is strictly Na+-dependent and chloride-independent.
"In transiently transfected COS cells, ileal Na(+)-bile acid cotransporter-mediated taurocholate uptake was strictly Na+ dependent and chloride independent."
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Both conjugated and unconjugated bile acids are efficiently transported.
"Analysis of the substrate specificity in transfected COS or CHO cells showed that both conjugated and unconjugated bile acids are efficiently transported."
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The ileal/renal carrier has a narrow specificity for bile acids, in explicit contrast to the multispecific liver carrier which handles organic anion metabolites and xenobiotics.
"Whereas the multispecific liver Na(+)-bile acid cotransporter may participate in hepatic clearance of organic anion metabolites and xenobiotics, the ileal and renal Na(+)-bile acid cotransporter retains a narrow specificity for reclamation of bile acids."
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The transcript is detected in terminal ileum and kidney, and the kidney cDNA is identical to the ileal one.
"Using Northern blot analysis to determine its tissue expression, we readily detected the ileal Na(+)-bile acid cotransporter mRNA in terminal ileum and kidney."
Bile acid uptake via the human apical sodium-bile acid cotransporter is electrogenic.
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Intestinal bile acid absorption depends on a sodium-bile acid cotransport protein located in the apical membrane of the ileal epithelial cell.
"Intestinal absorption of bile acids depends on a sodium-bile acid cotransport protein in the apical membrane of the ileal epithelial cell."
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Transport by the human apical transporter is electrogenic and bidirectional with a 2:1 Na+ to bile acid coupling stoichiometry, measured in voltage-clamped single cells.
"These results indicate that the cotransport of bile acids and Na+ by human apical sodium-bile acid transporter is electrogenic and bidirectional and is best explained by a 2:1 Na+:bile acid coupling stoichiometry."
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Lowering extracellular Na+ three-fold shifted the flux-voltage relationship by -52 mV, the shift expected for two Na+ per bile acid.
"A 3-fold reduction in extracellular Na+ produced a negative 52 mV shift of the flux-voltage relationship, consistent with a 2:1 Na+:bile acid coupling stoichiometry."
Topology scanning and putative three-dimensional structure of the extracellular binding domains of the apical sodium-dependent bile acid transporter (SLC10A2).
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ASBT facilitates the enterohepatic circulation of bile salts and is important for cholesterol metabolism.
"The apical sodium-dependent bile acid transporter (ASBT, SLC10A2) facilitates the enterohepatic circulation of bile salts and plays a key role in cholesterol metabolism."
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A seven-transmembrane topology was confirmed experimentally by glycosylation-scanning mutagenesis of inserted reporter sites.
"Membrane topology was further evaluated and confirmed by N-glycosylation-scanning mutagenesis, as reporter sites inserted in the putative extracellular loops 1 and 3 were glycosylated."
Bile acid transporters.
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Bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter after entering the small intestinal lumen.
"Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter."
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Beyond hepatocytes and enterocytes, members of this transporter group act in biliary, renal and colonic epithelium.
"In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles."
Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology.
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Conjugated bile salts enter primarily terminal ileal enterocytes through the apical sodium-dependent bile acid transporter encoded by SLC10A2, which is the first of four transporters of the enterohepatic cycle.
"conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium-dependent bile acid transporter (gene SLC10A2)"
A reference map of the human binary protein interactome.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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The study is a proteome-scale affinity-purification mass spectrometry survey (BioPlex 3.0 in 293T cells plus an HCT116 network), not a focused study of any one protein.
"Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks."
The solute carrier superfamily interactome.
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The study mapped protein-protein interactions of 396 solute carriers by interaction proteomics as a global survey, not as functional assignment for individual carriers.
"We aimed at obtaining a global survey of the SLC-protein interaction landscape and mapped the protein-protein interactions of 396 SLCs by interaction proteomics."
SLC10A2 transports bile salts and acids and Na+ from extracellular region to cytosol
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ASBT is expressed on the apical surface of enterocytes and its transport reaction is the first step of intestinal bile salt reabsorption.
"In the body, ASBT is expressed on the apical surfaces of enterocytes, and this reaction is the first step in the process by which bile salts and acids are reaborbed from the intestinal lumen and returned to the liver"
Recycling of bile acids and salts
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Recycling of bile acids begins with uptake by enterocytes mediated by ASBT (SLC10A2), followed by FABP6-mediated cytosolic traversal and basolateral efflux.
"This recycling involves a series of transport processes: uptake by enterocytes mediated by ASBT (SLC10A2), traversal of the enterocyte cytosol mediated by ileal bile acid binding protein (I-BABP - FABP6), efflux from enterocytes mediated by MRP3 (ABCC3)"
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods