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Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders.
Int J Mol Sci. 2018 Nov 14; 19(11)IJ

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.

Authors+Show Affiliations

Research School of Biology, Australian National University, Canberra, ACT 2601, Australia. kiran.javed@anu.edu.au.Research School of Biology, Australian National University, Canberra, ACT 2601, Australia. qi.cheng@anu.edu.au.ANU Joint Mass Spectrometry Facility, Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia. adam.carroll@anu.edu.au.ANU Joint Mass Spectrometry Facility, Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia. thy.truong@anu.edu.au.Research School of Biology, Australian National University, Canberra, ACT 2601, Australia. stefan.broeer@anu.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30441827

Citation

Javed, Kiran, et al. "Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders." International Journal of Molecular Sciences, vol. 19, no. 11, 2018.
Javed K, Cheng Q, Carroll AJ, et al. Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders. Int J Mol Sci. 2018;19(11).
Javed, K., Cheng, Q., Carroll, A. J., Truong, T. T., & Bröer, S. (2018). Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders. International Journal of Molecular Sciences, 19(11). https://doi.org/10.3390/ijms19113597
Javed K, et al. Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders. Int J Mol Sci. 2018 Nov 14;19(11) PubMed PMID: 30441827.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders. AU - Javed,Kiran, AU - Cheng,Qi, AU - Carroll,Adam J, AU - Truong,Thy T, AU - Bröer,Stefan, Y1 - 2018/11/14/ PY - 2018/09/27/received PY - 2018/11/07/revised PY - 2018/11/08/accepted PY - 2018/11/17/entrez PY - 2018/11/18/pubmed PY - 2019/2/12/medline KW - amino acid absorption KW - epithelial transport KW - metabolomics JF - International journal of molecular sciences JO - Int J Mol Sci VL - 19 IS - 11 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/30441827/Development_of_Biomarkers_for_Inhibition_of_SLC6A19_(B⁰AT1)-A_Potential_Target_to_Treat_Metabolic_Disorders L2 - http://www.mdpi.com/resolver?pii=ijms19113597 DB - PRIME DP - Unbound Medicine ER -