Defective intestinal amino acid absorption in Ace2 null mice.

Abstract

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.

• Authors: Dustin Singer, Simone M R Camargo, Tamara Ramadan, Matthias Schäfer, Luca Mariotta, Brigitte Herzog, Katja Huggel, David Wolfer, Sabine Werner, Josef M Penninger, François Verrey
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 303 Issue 6 Pg. G686-95 (Sep 15 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22790597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport Systems, Neutral
• Amino Acids
• Dietary Proteins
• SLC6A19 protein, mouse
• Niacin
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Absorption (physiology)
• Amino Acid Transport Systems, Neutral (genetics, metabolism)
• Amino Acids (metabolism)
• Angiotensin-Converting Enzyme 2
• Animal Nutritional Physiological Phenomena
• Animals
• Diet
• Dietary Proteins (administration & dosage)
• Gene Expression Regulation (physiology)
• Genotype
• Homeostasis
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Knockout
• Niacin (metabolism)
• Peptidyl-Dipeptidase A (genetics, metabolism)
• Time Factors