Remodeling of Lipid Metabolism by Dietary Restriction of Essential Amino Acids

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FIG. 1.
FIG. 1.

A model showing both global and gene-specific control of mRNA translation and gene transcription following sensing of EAA deficiency. One of the earliest sensing events involves phosphorylation of the protein factor eukaryotic initiation factor 2 (eIF2) by the highly conserved and ubiquitously expressed protein kinase GCN2. Phosphorylation of eIF2α by GCN2 produces a coordinated response that limits ribosomal translation of most mRNAs (35,43,52), while selectively derepressing the translation of specific genes containing specific upstream open reading frames. Through increased duration of ribosomal scanning and reinitiation efficiency (79), proteins such as activating transcription factor 4 (ATF4) are recruited to promoter regions of DNA, altering chromatin structure to enhance gene expression of other transcription factors (C/EBP homologous protein [CHOP], CCAAT/enhancer-binding protein-β, ATF3, ATF2) plus additional regulatory proteins such as asparagine synthetase, Tribbles homolog 3 (TRB3), and the histone demethylase Jumanji domain containing protein (JMJD3) (41,45,8082). ATF4 can heterodimerize with both CCAAT/enhancer-binding protein family members and other ATF members, forming multimeric complexes that bind CCAAT/enhancer-binding protein–ATF response elements, which serve as AAR elements (40,41). uORF, upstream open reading frame; ASNS, asparagine synthetase (ASNS); GADD34, growth arrest and DNA damage gene; PP5, protein phosphatase; SIRT1, sirtuin 1; GEF, guanine nucleotide exchange factor.

This Article

  1. Diabetes vol. 62 no. 8 2635-2644