Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders.
Development of Biomarkers for Inhibition of SLC6A19 (B⁰AT1)-A Potential Target to Treat Metabolic Disorders.
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DOI：
10.3390/ijms19113597
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发表时间：
2018-11-14
影响因子：
5.6
通讯作者：
Bröer S
中科院分区：
文献类型：
--
作者：
Javed K;Cheng Q;Carroll AJ;Truong TT;Bröer S
最近的研究已经确定，饮食蛋白质限制改善代谢健康和葡萄糖稳态。SLC 6A 19（B 0AT 1）是肠道中主要的中性氨基酸转运蛋白，并从饮食中吸收大部分氨基酸。缺乏SLC 6A 19的小鼠表现出蛋白质限制的迹象，具有改善的葡萄糖耐量，并且免受饮食诱导的肥胖。这种转运蛋白的药理学阻断可用于诱导蛋白质限制和治疗代谢疾病，如2型糖尿病。最近已经使用体外化合物筛选鉴定了一些新的SLC 6A 19抑制剂，但仍不清楚这些化合物是否在体内阻断转运蛋白。为了评价SLC 6A 19抑制剂的功效，需要能够可靠地检测小鼠中转运蛋白的成功抑制的生物标志物。使用基于气相色谱-质谱（GC-MS）的非靶向代谢组学方法来区分SLC 6A 19 ko和wt小鼠血浆、尿液和粪便样品中的总体代谢物谱。由于肠道吸收效率低，肾脏缺乏重吸收，在尿液和粪便样本中观察到氨基酸水平显著升高。相比之下，与其他生物样品相比，雄性SLC 6A 19 ko小鼠血浆中的一些中性氨基酸减少。细菌蛋白发酵代谢产物如对甲酚葡萄糖醛酸苷和3-吲哚丙酸在SLC 6A 19 ko小鼠中更丰富，表明膳食氨基酸的蛋白质吸收不良。一致地，与wt相比，在胃内施用氨基酸混合物后，SLC 6A 19 ko小鼠中[14 C]标记的中性氨基酸的血浆出现率延迟。受试者工作特征（ROC）曲线分析用于验证这些代谢物作为生物标志物的潜在用途。这些发现提供了推定的代谢物生物标志物，可用于检测蛋白质吸收不良和肠道和肾脏中该转运蛋白的抑制。
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.
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影响因子：
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作者：
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