title: The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator.
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-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.
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Clint D J
authors.initials: CD
authors.lastname: Tavares
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Kfir
authors.initials: K
authors.lastname: Sharabi
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: John E
authors.initials: JE
authors.lastname: Dominy
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Marta
authors.initials: M
authors.lastname: Isasa
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Orozco
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: From the Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and pere_puigserver@dfci.harvard.edu.
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D056945:Hep G2 Cells; D051548:Histone Acetyltransferases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008715:Methionine / Q000494:pharmacology*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D008715:Methionine; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse; C000589598:GCN5 histone acetyltransferase, mouse
keywords: acetylation; acetyltransferase; gluconeogenesis; glucose-6-phosphatase (G6pc); methionine; methionine transamination; methylthiopropionic acid (MTP); peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) (PPARGC1α); phosphoenolpyruvate carboxykinase (Pck1); transcription coactivator