T‐type amino acid transporter TAT1 (Slc16a10) is essential for extracellular aromatic amino acid homeostasis control

Abstract

Key points• The amino acid (AA) transporter TAT1 (Slc16A10) mediates facilitated diffusion of aromatic AAs (AAAs) across membranes.• TAT1 null mice lack liver control of AAAs and display altered epithelial AA transport.• The data support the hypothesis that equilibrative transport of essential AAs by TAT1 is crucial for body AA homeostasis control. AbstractThe uniporter TAT1 (Slc16a10) mediates the facilitated diffusion of aromatic amino acids (AAAs) across basolateral membranes of kidney, small intestine and liver epithelial cells, and across the plasma membrane of non-epithelial cells like skeletal myocytes. Its role for body AA homeostasis has now been investigated using newly generated TAT1 (Slc16a10) defective mice (tat1 −/− ). These mice grow and reproduce normally, show no gross phenotype and no obvious neurological defect. Histological analysis did not reveal abnormalities and there is no compensatory change in any tested AA transporter mRNA. TAT1 null mice, however, display increased plasma, muscle and kidney AAA concentration under both normal and high protein diet, although this concentration remains normal in the liver. A major aromatic aminoaciduria and a smaller urinary loss of all substrates additionally transported by L-type AA antiporter Lat2-4F2hc (Slc7a8) were revealed under a high protein diet. This suggests an epithelial transport defect as also shown by the accumulation of intravenously injected 123 I-2-I-L-Phe in kidney and L-[3 H]Phe in ex vivo everted gut sac enterocytes. Taken together, these data indicate that the uniporter TAT1 is required to equilibrate the concentration of AAAs across specific membranes. For instance, it enables hepatocytes to function as a sink that controls the extracellular AAAs concentration. Additionally, it facilitates the release of AAAs across the basolateral membrane of small intestine and proximal kidney tubule epithelial cells, thereby allowing the efflux of other neutral AAs presumably via Lat2-4F2hc.

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

“…SLC16A10 was also downregulated in NASH. In previous studies, deletion of SLC16A10 in rodent models resulted in an accumulation of plasma AAAs and decreased metabolism of AAA in the liver (Mariotta et al 2012). Thus, decreased gene expression of SLC16A10 may indicate a potential mechanism for the elevation of tyrosine and phenylalanine levels in our NASH samples.…”

“…SLC16A10 (TAT1) functions as a uniporter in the transport of AAAs across the basolateral membrane of liver epithelial cells (Mariotta et al 2012) while SLC43A1 (LAT3) is involved in the efflux of BCAAs from the liver to blood (Bodoy et al 2012; Fukuhara et al 2007). The transcriptomic profiling of alterations in amino acid metabolism and transporters during NAFLD progression will yield potential mechanistic clues for the biochemical alterations in BCAAs.…”

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

“…In contrast, the expression of the other y + L-type transporter y + LAT2 is very low, suggesting that this catalytic subunit is not of functional importance for the transepithelial cationic AA absorption. Furthermore, the mRNA expression of the basolateral AA transporters considered to be part of the neutral AA transport machinery (LAT2, LAT4 and TAT1) (Mariotta et al 2012) appear to be expressed at a lower level in the terminal ileum than in the duodenum and presumably the jejunum, in contrast to y + LAT1. This differential expression may reflect the fact that the largest load of neutral AAs is already absorbed before the ileum such that the efflux capacity of ileal enterocytes for neutral AAs is not anymore that high.…”

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

“…A tat1 knockout mouse model was produced by the ENU (N-ethyl-N-nitrosurea) mutagenesis (Ingenium Pharmaceuticals, Planegg, Germany). After 10 backcrossings in a C57Bl/6J background, the animals were used on the described experiments (Mariotta et al, 2012). For all the experiments, 4-to 5-month-old mice from both genders were used.…”

“…The neutral and dibasic AA exchanger (antiporter) b transporter responsible for cystine reabsorption in the kidney, but transports cationic as well as neutral AAs across the luminal enterocyte membrane (Bertran et al, 1992;Palacin et al, 1998Palacin et al, , 2005Feliubadalo et al, 1999;Pfeiffer et al, 1999;Dave et al, 2004). Among the basolateral enterocyte transporters, the AA exchangers y 1 LAT1-4F2hc and LAT2-4F2hc (SLC7A8-SLC3A2) (Pfeiffer et al, 1999;Rossier et al, 1999;Sperandeo et al, 2007) and the aromatic AA uniporter TAT1 (SLC16A10) (Kim et al, 2001;Quinones et al, 2004;Ramadan et al, 2006Ramadan et al, , 2007Mariotta et al, 2012) were shown to promote accumulation or efflux of AA from the enterocytes to the extracellular space. In addition, the functional interaction between different transporters can affect the net flux of AAs (Nguyen et al, 2007;Ramadan et al, 2007;Verrey et al, 2009).…”