Dataset Information

Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice.

ABSTRACT: High protein feeding has been shown to accelerate the development of type 1 diabetes in female non-obese diabetic (NOD) mice. Here, we investigated whether reducing systemic amino acid availability via knockout of the Slc6a19 gene encoding the system B(0) neutral amino acid transporter AT1 would reduce the incidence or delay the onset of type 1 diabetes in female NOD mice. Slc6a19 gene deficient NOD mice were generated using the CRISPR-Cas9 system which resulted in marked aminoaciduria. The incidence of diabetes by week 30 was 59.5% (22/37) and 69.0% (20/29) in NOD.Slc6a19+/+ and NOD.Slc6a19-/- mice, respectively (hazard ratio 0.77, 95% confidence interval 0.41-1.42; Mantel-Cox log rank test: p = 0.37). The median survival time without diabetes was 28 and 25 weeks for NOD.Slc6a19+/+ and NOD.Slc6a19-/- mice, respectively (ratio 1.1, 95% confidence interval 0.6-2.0). Histological analysis did not show differences in islet number or the degree of insulitis between wild type and Slc6a19 deficient NOD mice. We conclude that Slc6a19 deficiency does not prevent or delay the development of type 1 diabetes in female NOD mice.

SUBMITTER: Waters MF

PROVIDER: S-EPMC8540324 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice.

Waters Matthew F MF Delghingaro-Augusto Viviane V Javed Kiran K Dahlstrom Jane E JE Burgio Gaetan G Bröer Stefan S Nolan Christopher J CJ

Metabolites 20210929 10

High protein feeding has been shown to accelerate the development of type 1 diabetes in female non-obese diabetic (NOD) mice. Here, we investigated whether reducing systemic amino acid availability via knockout of the <i>Slc6a19</i> gene encoding the system B(0) neutral amino acid transporter AT1 would reduce the incidence or delay the onset of type 1 diabetes in female NOD mice. <i>Slc6a19</i> gene deficient NOD mice were generated using the CRISPR-Cas9 system which resulted in marked aminoacid ...[more]

PMID: 34677380

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Project description:B0AT1 (SLC6A19) is a major sodium-coupled neutral amino acid transporter that relies on angiotensin converting enzyme 2 (ACE2) or collectrin for membrane trafficking. Despite its significant role in disorders associated with amino acid metabolism, there is a deficit of comprehensive structure-function understanding of B0AT1 in lipid environment. Herein, we have employed molecular dynamics (MD) simulations to explore the architectural characteristics of B0AT1 in two distinct environments: a simplified POPC bilayer and a complex lipid system replicating the native membrane composition. Notably, our B0AT1 analysis in terms of structural stability and regions of maximum flexibility shows consistency in both the systems with enhanced structural features in the case of complex lipid system. Our findings suggest that diacylglycerol phospholipids significantly alter the pore radius, hydrophobic index, and surface charge distribution of B0AT1, thereby affecting the flexibility of transmembrane helices TM7, TM12, and loop connecting TM7-TM8, crucial for ACE2-B0AT1 interaction. Pro41, Ser190, Arg214, Arg240, Ser413, Pro414, Cys463, and Val582 are among the most prominent lipid binding residues that might influence B0AT1 functionality. We also perceive notable lipid mediated deviation in the degree of tilt and loss of helicity in TM1 and TM6 which might affect the substrate binding sites S1 and S2 in B0AT1. Considerably, destabilization in the structure of B0AT1 in lipid environment was evident upon mutation in TM domain, associated with Hartnup disorder through various structure-based protein stability tools. Our two-tiered approach allowed us to validate the use of POPC as a baseline for initial analyses of SLC transporters. Altogether, our all-atoms MD study provides a platform for future investigations into the structure-function mechanism of B0AT1 in realistic lipid mimetic bilayers and offers a framework for developing new therapeutic agents targeting this transporter.

Dataset Information

Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice.

Publications

Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice.

Similar Datasets

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