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Mice Lacking the Intestinal and Renal Neutral Amino Acid Transporter SLC6A19 Demonstrate the Relationship between Dietary Protein Intake and Amino Acid Malabsorption.

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.

SUBMITTER: Javed K

PROVIDER: S-EPMC6770948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control.

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The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition.

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Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases.

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Low temperature bacterial expression of the neutral amino acid transporters SLC1A5 (ASCT2), and SLC6A19 (B0AT1).

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Neutral amino acid transporter SNAT2 protects renal medulla from hypertonicity-induced ferroptosis

Project description:Hypertonicity in renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct cells (MCDs) survive and function under the harsh hypertonic stress remains incompletely understood. By using the RNA-seq technique, we identified SNAT2 (slc38a2) as a novel osmoresponsive neutral amino acid transporter in MCD cells. We found that hypertonic stress induced cell death of MCDs mainly via ferroptosis.

2023-02-15 | GSE206476 | GEO

Orphan transporter SLC6A18 is renal neutral amino acid transporter B0AT3.

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Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse.

Project description: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.

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Molecular basis of inhibition of the amino acid transporter B<sup>0</sup>AT1 (SLC6A19).

Project description:The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate B0AT1 inhibitors with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

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Na+ interactions with the neutral amino acid transporter ASCT1.

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