Development of Biomarkers for Inhibition of SLC6A19 (B0AT1)—A Potential Target to Treat Metabolic Disorders
| Autor: | Adam J. Carroll, Stefan Bröer, Kiran Javed, Qi Cheng, Thy T. Truong |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Metabolite amino acid absorption Catalysis Article Inorganic Chemistry lcsh:Chemistry 03 medical and health sciences chemistry.chemical_compound Mice Metabolomics Metabolic Diseases medicine Glucose homeostasis Animals Physical and Theoretical Chemistry Amino Acids Molecular Biology lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification Benztropine Kidney epithelial transport Reabsorption Organic Chemistry Transporter General Medicine Renal Reabsorption metabolomics 6. Clean water 3. Good health Computer Science Applications Amino acid Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Amino Acid Transport Systems Neutral chemistry Biochemistry Intestinal Absorption lcsh:Biology (General) lcsh:QD1-999 Metabolome Female Dietary Proteins Glucuronide Biomarkers |
| Zdroj: | International Journal of Molecular Sciences, Vol 19, Iss 11, p 3597 (2018) International Journal of Molecular Sciences Volume 19 Issue 11 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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