Citation:
Abstract:
Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1alpha to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1alpha acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1alpha acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1alpha acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1alpha-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1alpha acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo These results highlight a communication between methionine metabolism and PGC-1alpha-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.
Notes:
Tavares, Clint D JSharabi, KfirDominy, John ELee, YoonjinIsasa, MartaOrozco, Jose MJedrychowski, Mark PKamenecka, Theodore MGriffin, Patrick RGygi, Steven PPuigserver, PereengR24 DK080261/DK/NIDDK NIH HHS/T32 GM007753/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tJ Biol Chem. 2016 May 13;291(20):10635-45. doi: 10.1074/jbc.M115.706200. Epub 2016 Mar 28.