Amino acid limitation regulates gene expression

In mammals, the plasma concentration of amino acids is affected by nutritio nal or pathological conditions. For example, an alteration in the amino aci d profile has been reported when there is a deficiency of any one or more o f the essential amino acids, a dietary imbalance of amino acids, or an insu fficient intake of protein. We examined the role of amino acid limitation i n 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 concentratio n reproducing the amino acid concentration found in portal blood of rats fe d on a low-protein diet leads to a significantly higher (P<0.0002) expressi on of IGFBP-1. Using CCAAT/enhancer-binding protein homologous protein (CHO P) induction by leucine deprivation as a model, we have characterized the m olecular mechanisms involved in the regulation of gene expression by amino acids. We have shown that leucine limitation leads to induction of CHOP mRN A and protein. Elevated mRNA levels result from both an increase in the rat e of CHOP transcription and an increase in mRNA stability. We have characte rized two elements of the CHOP gene that are essential to the transcription al activation produced by an amino acid limitation. These findings demonstr ate that an amino acid limitation, as occurs during dietary protein deficie ncy, can induce gene expression. Thus, amino acids by themselves can play, in concert with hormones, an important role in the control of gene expressi on.