Institute of Physiology, University of Zurich, Switzerland.
Am J Physiol Gastrointest Liver Physiol. 2012 Sep 15;303(6):G686-95. doi: 10.1152/ajpgi.00140.2012. Epub 2012 Jul 12.
Mutations in the main intestinal and kidney luminal neutral amino acid transporter B(0)AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor L-tryptophan. Since Ace2 is necessary for intestinal B(0)AT1 expression, we tested the impact of intestinal B(0)AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na(+)-dependent uptake of B(0)AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na(+)-dependent transport of L-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more L-tryptophan than other B(0)AT1 substrates reach the ileum in wild-type mice, which is in line with its known lower apparent affinity. In ace2 null mice, the absorption defect was confirmed by a severalfold increase of L-tryptophan and of other neutral amino acids reaching the ileum lumen. Furthermore, plasma and muscle levels of glycine and L-tryptophan were significantly decreased in ace2 null mice, with other neutral amino acids displaying a similar trend. A low-protein/low-niacin diet challenge led to differential changes in plasma amino acid levels in both wild-type and ace2 null mice, but only in ace2 null mice to a stop in weight gain. Despite the combination of low-niacin with a low-protein diet, plasma niacin concentrations remained normal in ace2 null mice and no pellagra symptoms, such as photosensitive skin rash or ataxia, were observed. In summary, mice lacking Ace2-dependent intestinal amino acid transport display no total niacin deficiency nor clear pellagra symptoms, even under a low-protein and low-niacin diet, despite gross amino acid homeostasis alterations.
肠道和肾脏腔面中性氨基酸转运体 B(0)AT1（Slc6a19）的主要突变导致 Hartnup 病，其特征是中性氨基酸尿，在某些情况下还伴有糙皮病样症状。这些糙皮病样症状是由低烟酸引起的，被认为是由于肠道对其前体 L-色氨酸的吸收缺陷所致。由于 Ace2 对于肠道 B(0)AT1 的表达是必需的，我们测试了 ace2 缺失对肠道 B(0)AT1 缺失的影响。断奶后，它们的体重增加减少，并且在外翻肠环中测量的 B(0)AT1 底物的 Na(+)-依赖性摄取受损。此外，高亲和力的 Na(+)-依赖性 L-脯氨酸转运，推测通过 SIT1（Slc6a20），是不存在的，而通过 SGLT1（Slc5a1）的葡萄糖摄取不受影响。胃管给予后测量小肠腔腔氨基酸含量表明，与其他 B(0)AT1 底物相比，更多的 L-色氨酸到达野生型小鼠的回肠，这与已知的较低表观亲和力一致。在 ace2 缺失的小鼠中，L-色氨酸和其他中性氨基酸到达回肠腔的吸收缺陷通过数倍增加得到证实。此外，ace2 缺失的小鼠血浆和肌肉中的甘氨酸和 L-色氨酸水平显著降低，其他中性氨基酸也呈现出类似的趋势。低蛋白/低烟酸饮食挑战导致野生型和 ace2 缺失的小鼠血浆氨基酸水平发生差异变化，但仅在 ace2 缺失的小鼠中，体重增加停止。尽管低蛋白与低烟酸饮食相结合，但 ace2 缺失的小鼠血浆烟酸浓度保持正常，并且没有糙皮病症状，如光敏性皮疹或共济失调。总之，缺乏 Ace2 依赖性肠道氨基酸转运的小鼠即使在低蛋白和低烟酸饮食下也不会出现总烟酸缺乏或明显糙皮病症状，尽管存在严重的氨基酸内稳态改变。
