Genomic regulation of intestinal amino acid transporters by aldosterone

Abstract

Overexpression of renal LAT2, a Na+ -independent L-amino acid transporter, in spontaneous hypertensive rats (SHR) is organ specific and precedes the onset of hypertension (Pinho et al., Hypertension, 42:613-618, 2003). However, the expression of LAT2 correlates negatively with plasma aldosterone levels after high sodium intake (Pinho et al., Am J Physiol Ren Physiol 292:F1452-F1463, 2007). The present study evaluated the expression of Na+ -independent LAT1, LAT2, and 4F2hc and Na+ -dependent ASCT2 amino acid transporters in the intestine of normotensive Wistar rats chronically treated with aldosterone. In conditions of high salt intake, to keep endogenous aldosterone to a minimum, rats were implanted with aldosterone or spironolactone tablets. In aldosterone-treated and aldosterone + spironolactone-treated rats, aldosterone plasma levels were increased by fourfold. At the protein level, aldosterone treatment significantly increased LAT1 (62%), LAT2 (49%), 4F2hc (48%), and ASCT2 (65%) expression. The effect of aldosterone upon LAT1, LAT2, 4F2hc, and ASCT2 protein abundance was completely reversed by spironolactone. Aldosterone significantly increased intestinal LAT2 and 4F2hc mRNA levels (27% and 35% increase, respectively), with no changes in LAT1 and ASCT2 transcript levels. In conclusion, increases in intestinal Na+ -independent LAT1 and LAT2 and Na+ -dependent ASCT2 transcript and protein abundance during chronic treatment with aldosterone occur through a spironolactone-sensitive genomic mechanism.

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

“…In the rat intestine, leptin inhibits ASCT2 expression; interestingly the satiety hormone is involved in regulating the expression of several membrane transporters responsible for nutrient distribution (Ducroc et al, 2010 ). A positive regulation by aldosterone is also reported for rat ASCT2 in enterocytes overlapping that of LAT1, LAT2, and CD98, being in the frame of a concerted action toward nutrient transporters (Amaral et al, 2008 ). In mouse mammary gland, the ASCT2 expression is linked to GPCR that acts as mTOR dependent amino acid sensor and modulates the production of proteins in milk.…”

Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health

“…Low insulin concentration increases SLC7A5 /LAT1 mRNA abundance in an mTORC1-dependent manner in skeletal muscle cells (Walker et al, 2014). Lastly, LAT1 protein expression has been shown to be increased upon chronic treatment with aldosterone (Amaral et al, 2008). Much less is known about regulation of hLAT2 that responds like LAT1 to aldosterone stimulus (Amaral et al, 2008).…”

“…Lastly, LAT1 protein expression has been shown to be increased upon chronic treatment with aldosterone (Amaral et al, 2008). Much less is known about regulation of hLAT2 that responds like LAT1 to aldosterone stimulus (Amaral et al, 2008). A regulation of LAT2/4F2hc expression by mTORC1 has been described in glomerular epithelial cells: in glomerulonephritis conditions, mTORC1 integrates signals from inflammatory cytokines stimulating LAT2 translocation to plasma membrane (Kurayama et al, 2011).…”

Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring

“…The regulation of ASCT2 expression is under investigation since 2004 when it has been demonstrated that the glutamine availability, per se, regulates the expression of this transporter through a mechanism involving the transcription factor dimer FXR/RXR [149]. Then, some studies have been conducted in non-cancer models and positive regulation by EGF and aldosterone and negative regulation of ASCT2 expression by leptin in the intestine have been shown, [150].…”