The methionine transamination pathway controls hepatic glucose metabolism through regulation of the GCN5 acetyltransferase and the PGC-1α transcriptional coactivator

Clint D.J. Tavares, Kfir Sharabi, John E. Dominy, Yoonjin Lee, Marta Isasa, Jose M. Orozco, Mark P. Jedrychowski, Theodore M. Kamenecka, Patrick R. Griffin, Steven P. Gygi, Pere Puigserver*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 theGCN5acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1α to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1α 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-1α acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1α acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1α-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1α 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-1α-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.

Original languageAmerican English
Pages (from-to)10635-10645
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number20
DOIs
StatePublished - 13 May 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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