De Sousa-Coelho AL, Marrero PF, Haro D
Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 phosphorylation of eukaryotic initiation factor 2, global protein synthesis reduction and increased activating transcription factor (ATF) 4. ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 is induced during fasting in liver, and its expression induces a metabolic state that mimics long-term fasting. Thus, FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In this article, we show that FGF21 is induced by amino acid deprivation in both mouse liver and HepG2 cultured cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4 binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional program initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.