Cellular adaptation to amino acid availability: mechanisms involved in the regulation of gene expression.

Abstract

Abstract In mammals, the impact of nutrients on gene expression has become an important area of research. Nevertheless, the current understanding of amino acid-dependent control of gene expression is limited. Amino acids have multiple and important roles, so their homeostasis has to be finely maintained. However, the blood amino acid content can be affected by certain nutritional conditions or various forms of pathology. It follows that mammals have to adjust several of their physiological functions involved in the adaptation to amino acid availability by regulating expression of numerous genes. The aim of this review is to examine the role of amino acids in regulating mammalian gene expression and physiological functions. A limitation for several individual amino acids strongly increases the expression of target genes such as insulin-like growth factor-binding protein1 (IGFBP-1), C/EBP homologous protein (CHOP) and asparagine synthetase (ASNS) genes. The molecular mechanisms involved in the regulation of CHOP and ASNS gene transcription in response to amino acid starvation have been partly identified. In particular, a signalling pathway requiring the protein kinase general control non-depressive 2 (GCN2) and the activating transcription factor 4 (ATF4) has been described as sensing the amino acid limitation. In the case of an amino acid-imbalanced food source, this pathway has been shown to decrease food intake by activating a neuronal circuit. Taken together, the results discussed in this review demonstrate that amino acids by themselves can act as 'signal' molecules, with important roles in the control of gene expression and physiological functions.