Slc6a14-KO Mouse

Slc6a14, also known as amino acid transporter B0,+ (ATB0,+), is a Na+/Cl--coupled transporter that imports and concentrates all neutral amino acids as well as the two cationic acids lysine and arginine into the cytoplasm of different cell types [3,4]. It is involved in pathways such as glutaminolysis and the serine-glycine-one-carbon pathways which support cancer cell growth and proliferation [3]. It also plays a role in the anti-infective response and epithelial integrity in the airways [2]. Genetic models like KO mouse models can be valuable for studying its functions in vivo.

In ulcerative colitis, Slc6a14 knockdown suppressed ferroptosis, and it was found to facilitate ferroptosis by promoting C/EBPβ expression and binding activity to inhibit PAK6 expression [1]. In cystic fibrosis, it may modulate the anti-infective response and epithelial integrity of the airways, and its SNP rs3788766 is associated with lung disease severity, with the minor allele G being deleterious. Inhibition of Slc6a14 reduced 3H-arginine transport, mTOR phosphorylation, and bronchial epithelial repair rates [2,6]. In obesity-related studies, Slc6a14 -/- mice on a high-fat diet gained more weight, developed fatty liver and metabolic syndrome, suggesting a link between Slc6a14 deficiency and obesity under high-fat diet conditions [5].

In conclusion, Slc6a14 is crucial for amino acid transport and is involved in multiple biological processes and disease conditions. Gene knockout mouse models have revealed its role in ulcerative colitis, cystic fibrosis, and obesity-related metabolic syndrome, providing insights into the underlying mechanisms and potential therapeutic targets for these diseases.

References:

1. Chen, Yanjun, Yan, Wenying, Chen, Yuqi, Shi, Tongguo, Chen, Weichang. 2022. SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis. In Cellular and molecular life sciences : CMLS, 79, 563. doi:10.1007/s00018-022-04594-7. https://pubmed.ncbi.nlm.nih.gov/36272033/

2. Ruffin, M, Mercier, J, Calmel, C, Corvol, H, Guillot, L. 2020. [SLC6A14, a modifier gene in cystic fibrosis]. In Revue des maladies respiratoires, 37, 218-221. doi:10.1016/j.rmr.2020.02.008. https://pubmed.ncbi.nlm.nih.gov/32146055/

3. Sniegowski, Tyler, Korac, Ksenija, Bhutia, Yangzom D, Ganapathy, Vadivel. 2021. SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine-Glycine-One-Carbon Pathways in Cancer. In Pharmaceuticals (Basel, Switzerland), 14, . doi:10.3390/ph14030216. https://pubmed.ncbi.nlm.nih.gov/33806675/

4. Ruffin, Manon, Mercier, Julia, Calmel, Claire, Corvol, Harriet, Guillot, Loic. 2020. Update on SLC6A14 in lung and gastrointestinal physiology and physiopathology: focus on cystic fibrosis. In Cellular and molecular life sciences : CMLS, 77, 3311-3323. doi:10.1007/s00018-020-03487-x. https://pubmed.ncbi.nlm.nih.gov/32166393/

5. Sivaprakasam, Sathish, Sikder, Mohd O F, Ramalingam, Latha, Wachtel, Mitchell S, Ganapathy, Vadivel. 2021. SLC6A14 deficiency is linked to obesity, fatty liver, and metabolic syndrome but only under conditions of a high-fat diet. In Biochimica et biophysica acta. Molecular basis of disease, 1867, 166087. doi:10.1016/j.bbadis.2021.166087. https://pubmed.ncbi.nlm.nih.gov/33513428/

6. Mercier, Julia, Calmel, Claire, Mésinèle, Julie, Ruffin, Manon, Guillot, Loïc. 2022. SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity via mTOR and Epithelial Repair Modulation. In Frontiers in molecular biosciences, 9, 850261. doi:10.3389/fmolb.2022.850261. https://pubmed.ncbi.nlm.nih.gov/35372502/