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ABSTRACT: Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role
of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B0AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations
in SLC6A19. Na+-dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory
increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B0AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B0AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food
ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway
was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial
cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.
Journal of Biological Chemistry 07/2011; 286(30):26638-26651. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B(0)AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na(+)-dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B(0)AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B(0)AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.
Journal of Biological Chemistry 06/2011; 286(30):26638-51. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role
of epithelial neutral amino acid uptake in whole body homeostasis we analyzed mice lacking the apical broad-spectrum neutral
(0) amino acid transporter B0AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder, which is caused by mutations
in SLC6A19. Na+-dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory
increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B0AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B0AT1 deficient mice lost body weight rapidly on diets containing 6% or 40% protein. Secretion of insulin in response to food
ingestion after fasting was blunted. In the intestine, amino acid signalling to the mammalian target of rapamycin (mTOR) pathway
was reduced, while the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells.
The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.
Journal of Biological Chemistry 06/2011; · 4.77 Impact Factor
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ABSTRACT: Protein absorption in the intestine is mediated by proteases and brush-border peptidases together with peptide and amino acid transporters. Neutral amino acids are generated by a variety of aminopeptidases and carboxypeptidases and are subsequently taken up by the amino acid transporter B(0)AT1 (SLC6A19), which is mutated in Hartnup disorder. Coexpression of B(0)AT1 together with the brush-border carboxypeptidase angiotensin-converting enzyme 2 (ACE2) in Xenopus laevis oocytes led to a dramatic increase of transporter expression at the oocyte surface. Other members of the SLC6 family were not stimulated by coexpression with ACE2. Addition of a peptide containing a carboxyterminal leucine residue to ACE2- and B(0)AT1-coexpressing oocytes caused inward currents due to Na(+)-leucine cotransport, demonstrating the formation of a metabolic complex. Coexpression of the Hartnup disorder causing mutation B(0)AT1(R240Q) showed reduced interaction with ACE2 and its renal paralogue collectrin. This would result in reduced surface expression in both kidney and intestine, thereby explaining the onset of the disorder in individuals carrying this mutation.
The FASEB Journal 05/2008; 22(8):2880-7. · 5.71 Impact Factor
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ABSTRACT: Transporters of the SLC6 (solute carrier 6) family play an important role in the removal of neurotransmitters in brain tissue and in amino acid transport in epithelial cells. In the present study, we demonstrate that mouse v7-3 (slc6a15) encodes a transporter for neutral amino acids. The transporter is functionally and sequence related to B(0)AT1 (slc6a19) and was hence named B(0)AT2. Leucine, isoleucine, valine, proline and methionine were recognized by the transporter, with values of K(0.5) (half-saturation constant) ranging from 40 to 200 microM. Alanine, glutamine and phenylalanine were low-affinity substrates of the transporter, with K(0.5) values in the millimolar range. Transport of neutral amino acids via B(0)AT2 was Na+-dependent, Cl--independent and electrogenic. Superfusion of mouse B(0)AT2-expressing oocytes with amino acid substrates generated robust inward currents. Na+-activation kinetics of proline transport and uptake under voltage clamp suggested a 1:1 Na+/amino acid co-transport stoichiometry. Susbtrate and co-substrate influenced each other's K(0.5) values, suggesting that they share the same binding site. A mouse B(0)AT2-like transport activity was detected in synaptosomes and cultured neurons. A potential role of B(0)AT2 in transporting neurotransmitter precursors and neuromodulators is proposed.
Biochemical Journal 02/2006; 393(Pt 1):421-30. · 4.90 Impact Factor
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ABSTRACT: Neurotransmitter transporters of the SLC6 family play an important role in the removal of neurotransmitters in brain tissue and in amino acid transport in epithelial cells. Here we demonstrate that the mouse homologue of slc6a20 has all properties of the long-sought IMINO system. The mouse has two homologues corresponding to the single human SLC6A20 gene: these have been named XT3 and XT3s1. Expression of mouse XT3s1, but not XT3, in Xenopus laevis oocytes induced an electrogenic Na+-and-Cl--dependent transporter for proline, hydroxyproline, betaine, N-methylaminoisobutyric acid and pipecolic acid. Expression of XT3s1 was found in brain, kidney, small intestine, thymus, spleen and lung, whereas XT3 prevailed in kidney and lung. Accordingly we suggest that the two homologues be termed 'XT3s1 IMINO(B)' and 'XT3 IMINO(K)' to indicate the tissue expression of the two genes.
Biochemical Journal 04/2005; 386(Pt 3):417-22. · 4.90 Impact Factor
