Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner

• Published in: Biomolecules (Basel, Switzerland) Vol. 14; no. 9; p. 1160
• Main Authors: Schmidt, Alexandra V, Bharathi, Sivakama S, Solo, Keaton J, Bons, Joanna, Rose, Jacob P, Schilling, Birgit, Goetzman, Eric S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-09-2024; MDPI
• Subjects: Acetylation; Animals; Body fat; Cell cycle; Chromatography; Cytoplasm; Enzymes; Ethylenediaminetetraacetic acid; Female; Fitness equipment; Gluconeogenesis; Gluconeogenesis - genetics; Glucose; Glucose - metabolism; Glycolysis; Hepatocytes; Hepatocytes - metabolism; Hypoglycemia; Laboratory animals; Liver; Liver - metabolism; Lysine; Male; Males; Mass spectrometry; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Peptides; Phenotypes; Protein turnover; Proteins; Proteomics; Pyruvic acid; Scientific imaging; Sex Characteristics; Sex Factors; sirt-2; sirtuin; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Transcriptomes; Type 2 diabetes; United Kingdom; Missouri; St Louis Missouri; United Kingdom > UK; United States > US; glucose; metabolism; sirtuin; liver; gluconeogenesis; sirt-2
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14091160

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that
males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary
male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in
male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in
female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2's regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.