Defective intestinal amino acid absorption in Ace2 null mice.
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.
Institute of Physiology, University of Zurich, Switzerland.
Dustin
D
Singer
Simone M R
SM
Camargo
Tamara
T
Ramadan
Matthias
M
Schäfer
Luca
L
Mariotta
Brigitte
B
Herzog
Katja
K
Huggel
David
D
Wolfer
Sabine
S
Werner
Josef M
JM
Penninger
François
F
Verrey
D000042:Absorption / Q000502:physiology; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D004032:Diet; D004044:Dietary Proteins / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009525:Niacin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D026921:Amino Acid Transport Systems, Neutral; D000596:Amino Acids; D004044:Dietary Proteins; C505021:SLC6A19 protein, mouse; D009525:Niacin; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2