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-1␣ to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1␣ 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-1␣ acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1␣ acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1␣-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1␣ 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-1␣-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.Amino acid sensing is a critical mechanism that cells employ to maintain homeostasis and enable survival upon fluctuations in the nutritional environment (1, 2). Despite variability in side chain chemical structure, cells are able to distinguish the distinct amino acids through the use of specific tRNAs. The amino acid protein sensor GCN2 detects deficiencies in amino acids in a tRNA-dependent manner and reprograms cellular metabolism to modulate energy consumption and maintain homeostasis (3, 4). Although mTORC1 is not considered to be a direct sensor of amino acid levels, it functions similarly to GCN2 to alter metabolic pathways in response to amino acid deprivation (5). Methionine, a dietary essential amino acid, is among the more toxic of the L-amino acids, and hence its abundance needs to be precisely regulated (6, 7). The liver is the primary organ concerned with the detoxification of methionine, and hence its ability to sense alterations in concentrations of this amino acid is vital (8). The existence of any cross-talk between hepatic methionine metabolism and other nutrient-regulated metabolic processes in the liver, such as glucose production, requi...

Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB

“…Intriguingly, recent studies have shown that GCN5 is an important regulator of cell metabolism. In addition to being activated by its coenzyme acetyl-CoA, the acetyltransferase activity of GCN5 can also be up-regulated by the essential amino acid methionine and insulin-GSK3b signals [27][28][29]. In addition to being activated by its coenzyme acetyl-CoA, the acetyltransferase activity of GCN5 can also be up-regulated by the essential amino acid methionine and insulin-GSK3b signals [27][28][29].…”

Effect of herbal choline and rumen-protected methionine on lamb performance and blood metabolites

“…Some of these enzymes involved in the Met cycle are Met adenosyltransferase (1A MAT1a), and phosphatidylethanolamine methyltransferase (PEMT). Supplementation with RPC in cows has demonstrated that hepatic gene expression associated with antioxidant synthesis and DNA methylation status were improved (Osorio et al, 2014) and studies with liver hepatocytes from rodents show the relationship among the Met and hepatic glucose synthesis through PGC-1α (Tavares et al, 2016). The relationship between gluconeogenic factors and methylation affected by nutrition levels (Rattanatray et al, 2014) deserves more attention in ruminant studies.…”

“…Phosphatidylcholine participates in the synthesis and export of triglycerides in very low density lipoproteins (Zeisel, 2006) and this has affected plasma NEFA and cholesterol (Pinotti et al, 2003). Choline has increased liver glycogen (Piepenbrink & Overton, 2003) and Met transamination pathways promote the activation of the transcriptional coactivator PGC-1α, which is involved in the control of hepatic gluconeogenesis (Tavares et al, 2016); PGC-1α plays a central role in the regulation of cellular energy metabolism, (Liang & Ward, 2006).…”

Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α

“…Tris-HCl buffer (pH 7.4) served as a blank. All results were normalized to respective protein content [58]. …”

“…NAD+ concentrations were determined fluorometrically in dilutions of the supernatant sample using alcohol dehydrogenase (Sigma-Aldrich, St. Louis, MO). Excitation was at 339 nm, and emission wavelength was at 460 nm in a spectrofluorimeter (Spectra MaxGeminiXS, Sunnyvale, CA) [58]. …”