Leucine, glutamine, and tyrosine reciprocally modulate the translation initiation factors eIF4F and eIF2B in perfused rat liver

Leucine, glutamine, and tyrosine, three amino acids playing key modulatory roles in hepatic proteolysis, were evaluated for activation of signaling pa thways involved in regulation of liver protein synthesis. Furthermore, beca use leucine signals to effecters that lie distal to the mammalian target of rapamycin, these downstream factors were selected for study as candidate m ediators of amino acid signaling. Using the perfused rat liver as a model s ystem, we observed a 25% stimulation of protein synthesis in response to ba lanced hyperaminoacidemia, whereas amino acid imbalance due to elevated con centrations of leucine, glutamine, and tyrosine resulted in a protein synth etic depression of roughly 50% compared with normoaminoacidemic controls. T he reduction in protein synthesis accompanying amino acid imbalance became manifest at high physiologic concentrations and was dictated by the guanine nucleotide exchange activity of translation initiation factor eIF2B. Parad oxically, this phenomenon occurred concomitantly with assembly of the mRNA cap recognition complex, eIF4F as well as activation of the 70-kDa ribosoma l S6 kinase, p70(S6k). Dual and reciprocal modulation of eIF4F and eIF2B wa s leucine-specific because isoleucine, a structural analog, was ineffective in these regards. Thus, we conclude that amino acid imbalance, heralded by leucine, initiates a liver-specific translational failsafe mechanism that deters protein synthesis under unfavorable circumstances despite promotion of the eIF4F complex.