Amino acid limitation regulates gene expression

Abstract

In mammals, the plasma concentration of amino acids is affected by nutritional or pathological conditions. For example, an alteration in the amino acid profile has been reported when there is a deficiency of any one or more of the essential amino acids, a dietary imbalance of amino acids, or an insufficient intake of protein. We examined the role of amino acid limitation in regulating mammalian gene expression. Depletion of arginine, cystine and all essential amino acids leads to induction of insulin-like growth factor-binding protein-1 (IGFBP-1) mRNA and protein expression in a dose-dependent manner. Moreover, exposure of HepG2 cells to amino acids at a concentration reproducing the amino acid concentration found in portal blood of rats fed on a low-protein diet leads to a significantly higher (P < 0·0002) expression of IGFBP-1. Using CCAAT/enhancer-binding protein homologous protein (CHOP) induction by leucine deprivation as a model, we have characterized the molecular mechanisms involved in the regulation of gene expression by amino acids. We have shown that leucine limitation leads to induction of CHOP mRNA and protein. Elevated mRNA levels result from both an increase in the rate of CHOP transcription and an increase in mRNA stability. We have characterized two elements of the CHOP gene that are essential to the transcriptional activation produced by an amino acid limitation. These findings demonstrate that an amino acid limitation, as occurs during dietary protein deficiency, can induce gene expression. Thus, amino acids by themselves can play, in concert with hormones, an important role in the control of gene expression.

Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation

“…3A). This is contrary to the response detected for other genes regulated by depletion of essential AA, in that these genes can respond to single or complete AA deprivation (42,43). In fact, we know of no other gene regulated by AA deprivation that is not induced in response to complete AA depletion.…”

“…Our findings indicate that Gln is the only AA that, when added back to EBSS, is able to re-establish the induction of MnSOD mRNA levels. To further address the specificity of this response, we also evaluated asparagine synthetase (ASNS) (3,42,43), a gene known to be induced by both single and complete AA deprivation (Fig. 3, A and B).…”

“…Amino acid control of gene expression has been described at many levels, including transcription, translation, and mRNA stability (3,42). To help elucidate the mechanism of increased MnSOD mRNA levels, in response to amino acid deprivation, we measured heterogeneous nuclear RNA levels for MnSOD (66).…”

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

“…The absence of other amino acid such as leucine have been associated with an increase in the synthesis and stability of mRNA for CHOP (37). This gene encodes a transcription factor that interacts with CCAAT/enhancer-binding proteins family, which in turn may inhibit the normal proliferation of cells (38). Therefore, essential amino acids appear to induce changes in T cells that ultimately inhibit their normal proliferation.…”

Branched chain amino acids and metabolic regulation

“…Various strategies have been proposed to treat obesity by promoting fat mobilization, increasing energy expenditure, and/or reducing food intake [1,7]. Accumulating evidence has shown that diets with higher protein and reduced carbohydrates are beneficial for weight loss and increase loss of body fat [8][9][10]. Because leucine can interact with the insulin-signaling pathway and appears to regulate the oxidative use of glucose by skeletal muscle through stimulation of glucose recycling via the glucose-alanine cycle, the key to understanding the relationship between dietary protein and carbohydrates is the relationship between the intake of leucine and glucose [11].…”