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Stefan Broer - One of the best experts on this subject based on the ideXlab platform.

  • Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases.
    Frontiers in pharmacology, 2020
    Co-Authors: Aditya Yadav, Indrapal Singh Aidhen, Praveen Kumar Tiwari, Kiran Javed, Qi Cheng, Nishank Shah, Stefan Broer
    Abstract:

    Lack of B0AT1 (SLC6A19) partially protects mice against the onset of non-alcoholic steatohepatitis (NASH). To achieve a similar outcome through pharmacological treatment, we improved previously identified inhibitors of B0AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B0AT1 with IC50 values ranging from 8-90 μM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC50 of 1-15 μM) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to B0AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.

  • Mice Lacking the Intestinal and Renal Neutral Amino Acid Transporter SLC6A19 Demonstrate the Relationship between Dietary Protein Intake and Amino Acid Malabsorption.
    Nutrients, 2019
    Co-Authors: Kiran Javed, Stefan Broer
    Abstract:

    Dietary protein restriction has beneficial impacts on metabolic health. B0AT1 (SLC6A19) is the major transporter of neutral amino acids at the intestinal epithelia and absorbs the bulk of the diet-derived neutral amino acids from the intestinal lumen. It also reabsorbs neutral amino acids in the renal proximal tubules. Mice lacking B0AT1 show cellular outcomes of protein restriction, such as high FGF21 levels and low mTORC1 activity. Moreover, they have improved glucose homeostasis and resist diet-induced obesity. In this study, we investigated the relationship between protein restriction and dietary protein intake in C57Bl6/J wild-type (wt) and SLC6A19-knockout (SLC6A19ko) mice. When SLC6A19ko mice were fed diets containing 5%, 25%, or 52% of their total calories derived from protein, no differences in food intake or weight gain were observed. All essential amino acids significantly positively correlated with increasing dietary casein content in the wt mice. The SLC6A19ko mice showed reduced postprandial levels of essential amino acids in plasma, particularly following high-protein diets. Upon fasting, essential amino acids were the same in the wt and SLC6A19ko mice due to reduced amino acid catabolism. Bacterial metabolites originating from amino acid fermentation correlated with the dietary protein content, but showed a complex profile in the blood of the SLC6A19ko mice. This study highlights the potential of SLC6A19 as a knock-out or inhibition target to induce protein restriction for the treatment of metabolic disorders.

  • Development of Biomarkers for Inhibition of SLC6A19 (B0AT1)—A Potential Target to Treat Metabolic Disorders
    International journal of molecular sciences, 2018
    Co-Authors: Kiran Javed, Qi Cheng, Adam J. Carroll, Thy T. Truong, Stefan Broer
    Abstract:

    Recent studies have established that dietary protein restriction improves metabolic health and glucose homeostasis. SLC6A19 (B⁰AT1) is the major neutral amino acid transporter in the intestine and carries out the bulk of amino acid absorption from the diet. Mice lacking SLC6A19 show signs of protein restriction, have improved glucose tolerance, and are protected from diet-induced obesity. Pharmacological blockage of this transporter could be used to induce protein restriction and to treat metabolic diseases such as type 2 diabetes. A few novel inhibitors of SLC6A19 have recently been identified using in vitro compound screening, but it remains unclear whether these compounds block the transporter in vivo. To evaluate the efficacy of SLC6A19 inhibitors biomarkers are required that can reliably detect successful inhibition of the transporter in mice. A gas chromatography mass spectrometry (GC-MS)-based untargeted metabolomics approach was used to discriminate global metabolite profiles in plasma, urine and faecal samples from SLC6A19ko and wt mice. Due to inefficient absorption in the intestine and lack of reabsorption in the kidney, significantly elevated amino acids levels were observed in urine and faecal samples. By contrast, a few neutral amino acids were reduced in the plasma of male SLC6A19ko mice as compared to other biological samples. Metabolites of bacterial protein fermentation such as p-cresol glucuronide and 3-indole-propionic acid were more abundant in SLC6A19ko mice, indicating protein malabsorption of dietary amino acids. Consistently, plasma appearance rates of [14C]-labelled neutral amino acids were delayed in SLC6A19ko mice as compared to wt after intra-gastric administration of a mixture of amino acids. Receiver operating characteristic (ROC) curve analysis was used to validate the potential use of these metabolites as biomarkers. These findings provide putative metabolite biomarkers that can be used to detect protein malabsorption and the inhibition of this transporter in intestine and kidney.

  • development of biomarkers for inhibition of SLC6A19 b at1 a potential target to treat metabolic disorders
    International Journal of Molecular Sciences, 2018
    Co-Authors: Kiran Javed, Qi Cheng, Adam J. Carroll, Thy T. Truong, Stefan Broer
    Abstract:

    Recent studies have established that dietary protein restriction improves metabolic health and glucose homeostasis. SLC6A19 (B⁰AT1) is the major neutral amino acid transporter in the intestine and carries out the bulk of amino acid absorption from the diet. Mice lacking SLC6A19 show signs of protein restriction, have improved glucose tolerance, and are protected from diet-induced obesity. Pharmacological blockage of this transporter could be used to induce protein restriction and to treat metabolic diseases such as type 2 diabetes. A few novel inhibitors of SLC6A19 have recently been identified using in vitro compound screening, but it remains unclear whether these compounds block the transporter in vivo. To evaluate the efficacy of SLC6A19 inhibitors biomarkers are required that can reliably detect successful inhibition of the transporter in mice. A gas chromatography mass spectrometry (GC-MS)-based untargeted metabolomics approach was used to discriminate global metabolite profiles in plasma, urine and faecal samples from SLC6A19ko and wt mice. Due to inefficient absorption in the intestine and lack of reabsorption in the kidney, significantly elevated amino acids levels were observed in urine and faecal samples. By contrast, a few neutral amino acids were reduced in the plasma of male SLC6A19ko mice as compared to other biological samples. Metabolites of bacterial protein fermentation such as p-cresol glucuronide and 3-indole-propionic acid were more abundant in SLC6A19ko mice, indicating protein malabsorption of dietary amino acids. Consistently, plasma appearance rates of [14C]-labelled neutral amino acids were delayed in SLC6A19ko mice as compared to wt after intra-gastric administration of a mixture of amino acids. Receiver operating characteristic (ROC) curve analysis was used to validate the potential use of these metabolites as biomarkers. These findings provide putative metabolite biomarkers that can be used to detect protein malabsorption and the inhibition of this transporter in intestine and kidney.

  • Mice lacking neutral amino acid transporter B0AT1 (SLC6A19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control
    Molecular metabolism, 2015
    Co-Authors: Angelika Broer, Yang Jiang, Adam J. Rose, Tjeerd P. Sijmonsma, Anja Pfenninger, Stephan Herzig, Dieter Schmoll, Stefan Broer
    Abstract:

    Objective Type 2 diabetes arises from insulin resistance of peripheral tissues followed by dysfunction of β-cells in the pancreas due to metabolic stress. Both depletion and supplementation of neutral amino acids have been discussed as strategies to improve insulin sensitivity. Here we characterise mice lacking the intestinal and renal neutral amino acid transporter B0AT1 (SLC6A19) as a model to study the consequences of selective depletion of neutral amino acids.

Angelika Broer - One of the best experts on this subject based on the ideXlab platform.

  • Mice lacking neutral amino acid transporter B0AT1 (SLC6A19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control
    Molecular metabolism, 2015
    Co-Authors: Angelika Broer, Yang Jiang, Adam J. Rose, Tjeerd P. Sijmonsma, Anja Pfenninger, Stephan Herzig, Dieter Schmoll, Stefan Broer
    Abstract:

    Objective Type 2 diabetes arises from insulin resistance of peripheral tissues followed by dysfunction of β-cells in the pancreas due to metabolic stress. Both depletion and supplementation of neutral amino acids have been discussed as strategies to improve insulin sensitivity. Here we characterise mice lacking the intestinal and renal neutral amino acid transporter B0AT1 (SLC6A19) as a model to study the consequences of selective depletion of neutral amino acids.

  • Enterocyte-specific regulation of the apical nutrient transporter SLC6A19 (B0AT1) by transcriptional and epigenetic networks
    The Journal of biological chemistry, 2013
    Co-Authors: Emrah Tümer, Angelika Broer, Sarojini Balkrishna, Torsten Jülich, Stefan Broer
    Abstract:

    Enterocytes are specialized to absorb nutrients from the lumen of the small intestine by expressing a select set of genes to maximize the uptake of nutrients. They develop from stem cells in the crypt and differentiate into mature enterocytes while moving along the crypt-villus axis. Using the SLC6A19 gene as an example, encoding the neutral amino acid transporter B(0)AT1, we studied regulation of the gene by transcription factors and epigenetic factors in the intestine. To investigate this question, we used a fractionation method to separate mature enterocytes from crypt cells and analyzed gene expression. Transcription factors HNF1a and HNF4a activate transcription of the SLC6A19 gene in villus enterocytes, whereas high levels of SOX9 repress expression in the crypts. CpG dinucleotides in the proximal promoter were highly methylated in the crypt and fully de-methylated in the villus. Furthermore, histone modification H3K27Ac, indicating an active promoter, was prevalent in villus cells but barely detectable in crypt cells. The results suggest that SLC6A19 expression in the intestine is regulated at three different levels involving promoter methylation, histone modification, and opposing transcription factors.

  • intestinal peptidases form functional complexes with the neutral amino acid transporter b 0 at1
    Biochemical Journal, 2012
    Co-Authors: Stephen J. Fairweather, Angelika Broer, Megan L Omara, Stefan Broer
    Abstract:

    The brush-border membrane of the small intestine and kidney proximal tubule are the major sites for the absorption and re-absorption of nutrients in the body respectively. Transport of amino acids is mediated through the action of numerous secondary active transporters. In the mouse, neutral amino acids are transported by B0AT1 [broad neutral (0) amino acid transporter 1; SLC6A19 (solute carrier family 6 member 19)] in the intestine and by B0AT1 and B0AT3 (SLC6A18) in the kidney. Immunoprecipitation and Blue native electrophoresis of intestinal brush-border membrane proteins revealed that B0AT1 forms complexes with two peptidases, APN (aminopeptidase N/CD13) and ACE2 (angiotensin-converting enzyme 2). Physiological characterization of B0AT1 expressed together with these peptidases in Xenopus laevis oocytes revealed that APN increased the substrate affinity of the transporter up to 2.5-fold and also increased its surface expression (Vmax). Peptide competition experiments, in silico modelling and site-directed mutagenesis of APN suggest that the catalytic site of the peptidase is involved in the observed changes of B0AT1 apparent substrate affinity, possibly by increasing the local substrate concentration. These results provide evidence for the existence of B0AT1-containing digestive complexes in the brush-border membrane, interacting differentially with various peptidases, and responding to the dynamic needs of nutrient absorption in the intestine and kidney.

  • impaired nutrient signaling and body weight control in a na neutral amino acid cotransporter SLC6A19 deficient mouse
    Journal of Biological Chemistry, 2011
    Co-Authors: Angelika Broer, Jessica M. Vanslambrouck, Jeff Holst, Charles G. Bailey, John E J Rasko, Nadine Tietze, Torsten Juelich, Peter S. Solomon, Stefan Broer
    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.

  • Characterization of mouse amino acid transporter B0AT1 (SLC6A19).
    The Biochemical journal, 2005
    Co-Authors: Christoph Böhmer, Angelika Broer, John E J Rasko, Florian Lang, Sonja Kowalczuk, Michael Munzinger, Stefan Broer
    Abstract:

    The mechanism of the mouse (m)B0AT1 (SLC6A19) transporter was studied in detail using two electrode voltage-clamp techniques and tracer studies in the Xenopus oocyte expression system. All neutral amino acids induced inward currents at physiological potentials, but large neutral non-aromatic amino acids were the preferred substrates of mB0AT1. Substrates were transported with K0.5 values ranging from approx. 1 mM to approx. 10 mM. The transporter mediates Na+-amino acid co-transport with a stoichiometry of 1:1. No other ions were involved in the transport mechanism. An increase in the extracellular Na+ concentration reduced the K0.5 for leucine, and vice versa. Moreover, the K0.5 values and Vmax values of both substrates varied with the membrane potential. As a result, K0.5 and Vmax values are a complex function of the concentration of substrate and co-substrate and the membrane potential. A model is presented assuming random binding order and a positive charge associated with the ternary [Na+-substrate-transporter] complex, which is consistent with the experimental data.

Chengbo Yang - One of the best experts on this subject based on the ideXlab platform.

  • expression of apical na l glutamine co transport activity b0 system neutral amino acid co transporter b0at1 and angiotensin converting enzyme 2 along the jejunal crypt villus axis in young pigs fed a liquid formula
    Amino Acids, 2016
    Co-Authors: Dale Lackeyram, Zirong Wang, Todd C. Rideout, Chengbo Yang, B Stoll, Xiaojian Yang, Yulong Yin
    Abstract:

    Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B0 Na+–neutral AA co-transporter (B0AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including l-Gln, we hypothesized that high apical Na+–Gln co-transport activity, and B0AT1 (SLC6A19) in co-expression with angiotensin-converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt–villus axis in young animals via unique control mechanisms. Kinetics of Na+–Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt–villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na+–Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na+–Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B0AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40–47 %) than in the villus cells. There were no significant differences in B0AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na+–neutral AA uptake activities via abundantly co-expressing B0AT1 and ACE2 proteins in the apical membrane and by transcribing the B0AT1 (SLC6A19) gene in the epithelia along the entire crypt–villus axis.

  • expression of apical na l glutamine co transport activity b 0 system neutral amino acid co transporter b 0 at1 and angiotensin converting enzyme 2 along the jejunal crypt villus axis in young pigs fed a liquid formula
    Amino Acids, 2016
    Co-Authors: Dale Lackeyram, Zirong Wang, Todd C. Rideout, Chengbo Yang, B Stoll, Xiaojian Yang, Yulong Yin
    Abstract:

    Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B(0) Na(+)-neutral AA co-transporter (B(0)AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including L-Gln, we hypothesized that high apical Na(+)-Gln co-transport activity, and B(0)AT1 (SLC6A19) in co-expression with angiotensin-converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt-villus axis in young animals via unique control mechanisms. Kinetics of Na(+)-Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt-villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na(+)-Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na(+)-Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B(0)AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40-47 %) than in the villus cells. There were no significant differences in B(0)AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na(+)-neutral AA uptake activities via abundantly co-expressing B(0)AT1 and ACE2 proteins in the apical membrane and by transcribing the B(0)AT1 (SLC6A19) gene in the epithelia along the entire crypt-villus axis.

Yulong Yin - One of the best experts on this subject based on the ideXlab platform.

  • effects of vitamin b6 on growth diarrhea rate intestinal morphology function and inflammatory factors expression in a high protein diet fed to weaned piglets1
    Journal of Animal Science, 2019
    Co-Authors: Yulong Yin, Huansheng Yang, Lanmei Yin, Lei Wang, Pengfei Huang
    Abstract:

    Vitamin B6 (VB6) is an important coenzyme factor which participates in many metabolic reactions, especially amino acid metabolism. There are few reports on how VB6 mediates weaned piglet intestinal health. This study purposed to investigate dietary VB6 effects on growth, diarrhea rates, and intestinal morphology and function in weaned piglets fed a high-crude protein (22% CP) diet. Eighteen 21-d-old weaned [(Yorkshire × Landrace) × Duroc] piglets with body weights of 7.03 ± 0.15 (means ± SEM) kg were randomly assigned into 3 VB6-containing dietary treatments. Vitamin B6 content was: 0, 4, and 7 mg/kg, respectively. The feeding period lasted 14 d. The results showed that no significant difference existed for the growth performance. The 7 mg/kg VB6 group had a tendency to decrease diarrhea rate (P = 0.065). Blood biochemical parameters analysis demonstrated that total protein, cholesterol, and high-density lipoprotein significantly increased in the 7 mg/kg VB6 group (P < 0.05). In the jejunum, no significant differences were detected for villus height, villus width, crypt depth, villus height and crypt depth ratios, and positive Ki67 counts and the mRNA expression of inflammatory cytokines. Vitamin B6 significantly increased the mRNA expression of SLC6A19 and SLC6A20 (P < 0.05) and decreased the mRNA expression of SLC36A1 (P < 0.05). In the ileum, VB6 significantly increased villus height and villus width (P < 0.05) while decreased positive Ki67 cell counts for 7 mg/kg VB6 group (P < 0.05). Vitamin B6 had significantly increased the mRNA expression of interleukin-1β, tumor necrosis factor-α,cyclo-oxygen-ase-2, and transforming growth factor-β (P < 0.05). Vitamin B6 also had significantly increased mRNA expression of SLC6A19, SLC7A6, SLC7A7, and SLC36A1 (P < 0.05). These findings suggest that dietary supplementation with VB6 may affect the intestinal morphology and absorption and metabolism of protein in weaned piglets fed a high-protein diet by altering the expression of intestinal inflammatory cytokines and amino acid transporters.

  • effects of glutamate and aspartate on growth performance serum amino acids and amino acid transporters in piglets
    Food and Agricultural Immunology, 2018
    Co-Authors: Hui Han, Jie Yin, Xiaotong Zhu, Jie Zheng, Yulong Yin
    Abstract:

    ABSTRACTThis study mainly investigated the effects of different dietary levels of glutamate (Glu) and aspartate (Asp) on growth performance, blood amino acids, and amino acid transporters in piglets. Forty-two healthy piglets were randomly divided into six groups (n = 7): a control group in which piglets were fed 2.9% Glu and 1.5% Asp and other groups in which piglets received 1.3% or 1.7% Asp and 2.6%, 3.2%, or 3.5% Glu for 21 days. Growth performance, serum amino acid profiles from the mesenteric vein, portal vein, and anterior vena cava, and amino acid transporters in the liver were determined. The results showed that lower doses of Asp promoted growth and enhanced the amino acids, while high doses of Asp and Glu reduced growth and the amino acid pool in piglets (P < 0.05). Meanwhile, 3.2% Glu increased branched chain amino acids in the portal vein and anterior vena cava (P < 0.05). 3.5% Glu downregulated SLC7A1, SLC7A7, and SLC6A19 expression in the liver (P < 0.05). Collectively, these results indica...

  • expression of apical na l glutamine co transport activity b0 system neutral amino acid co transporter b0at1 and angiotensin converting enzyme 2 along the jejunal crypt villus axis in young pigs fed a liquid formula
    Amino Acids, 2016
    Co-Authors: Dale Lackeyram, Zirong Wang, Todd C. Rideout, Chengbo Yang, B Stoll, Xiaojian Yang, Yulong Yin
    Abstract:

    Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B0 Na+–neutral AA co-transporter (B0AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including l-Gln, we hypothesized that high apical Na+–Gln co-transport activity, and B0AT1 (SLC6A19) in co-expression with angiotensin-converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt–villus axis in young animals via unique control mechanisms. Kinetics of Na+–Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt–villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na+–Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na+–Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B0AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40–47 %) than in the villus cells. There were no significant differences in B0AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na+–neutral AA uptake activities via abundantly co-expressing B0AT1 and ACE2 proteins in the apical membrane and by transcribing the B0AT1 (SLC6A19) gene in the epithelia along the entire crypt–villus axis.

  • expression of apical na l glutamine co transport activity b 0 system neutral amino acid co transporter b 0 at1 and angiotensin converting enzyme 2 along the jejunal crypt villus axis in young pigs fed a liquid formula
    Amino Acids, 2016
    Co-Authors: Dale Lackeyram, Zirong Wang, Todd C. Rideout, Chengbo Yang, B Stoll, Xiaojian Yang, Yulong Yin
    Abstract:

    Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B(0) Na(+)-neutral AA co-transporter (B(0)AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including L-Gln, we hypothesized that high apical Na(+)-Gln co-transport activity, and B(0)AT1 (SLC6A19) in co-expression with angiotensin-converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt-villus axis in young animals via unique control mechanisms. Kinetics of Na(+)-Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt-villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na(+)-Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na(+)-Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B(0)AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40-47 %) than in the villus cells. There were no significant differences in B(0)AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na(+)-neutral AA uptake activities via abundantly co-expressing B(0)AT1 and ACE2 proteins in the apical membrane and by transcribing the B(0)AT1 (SLC6A19) gene in the epithelia along the entire crypt-villus axis.

Philippe Froguel - One of the best experts on this subject based on the ideXlab platform.

  • Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians.
    Diabetes, 2004
    Co-Authors: Emmanuelle Durand, Philippe Boutin, David Meyre, Karine Clement, Christian Dina, Marie-aline Charles, Philippe Froguel
    Abstract:

    Positional candidate gene analysis of the obesity-linked chromosome Xq24 locus identified two obesity-associated single nucleotide polymorphisms (SNPs) in the membrane amino acid transporter encoding the SLC6A14 (solute carrier family 6 [neurotransmitter transporter], member 14) gene in the Finnish population. Since we previously reported a modest evidence of linkage for this region in French obese families, we analyzed these SNPs in 1,267 obese adult case and 649 lean control subjects. SNPs 20649 C>T (odds ratio 1.23, 95% CI 1.04-1.45; P = 0.013) and 22510 C>G (1.36, 1.16-1.59; P = 0.0001) were shown to be associated with obesity in the French population. In addition, pedigree disequilibrium test results showed a modest excess of both at-risk SNP alleles in affected offspring (P = 0.05 and P = 0.08 for SNPs 20649 C>T and 22510 C>G, respectively). The SNP 22510 C>G at-risk G allele was associated, both in adult women with moderate obesity and in 234 obese girls, with higher body fat and modified perception of hunger and satiety (0.003 < P < 0.06). In conclusion, these data confirm an association of the SLC6A14 gene locus with obesity.

  • polymorphisms in the amino acid transporter solute carrier family 6 neurotransmitter transporter member 14 gene contribute to polygenic obesity in
    2004
    Co-Authors: Emmanuelle Durand, Philippe Boutin, David Meyre, Aline M Charles, Karine Clement, Christian Dina, Philippe Froguel
    Abstract:

    Positional candidate gene analysis of the obesity-linked chromosome Xq24 locus identified two obesity-associated single nucleotide polymorphisms (SNPs) in the membrane amino acid transporter encoding the SLC6A14 (solute carrier family 6 [neurotransmitter transporter], member 14) gene in the Finnish population. Since we previously reported a modest evidence of linkage for this region in French obese families, we analyzed these SNPs in 1,267 obese adult case and 649 lean control subjects. SNPs 20649 C>T (odds ratio 1.23, 95% CI 1.04 ‐1.45; P 0.013) and 22510 C>G (1.36, 1.16 ‐1.59; P 0.0001) were shown to be associated with obesity in the French population. In addition, pedigree disequilibrium test results showed a modest excess of both at-risk SNP alleles in affected offspring (P 0.05 and P 0.08 for SNPs 20649 C>T and 22510 C>G, respectively). The SNP 22510 C>G at-risk G allele was associated, both in adult women with moderate obesity and in 234 obese girls, with higher body fat and modified perception of hunger and satiety (0.003 < P < 0.06). In conclusion, these data confirm an association of the SLC6A14 gene locus with obesity. Diabetes 53:2483‐2486, 2004