Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner
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 <i>Sirt2−/−</i> males, but not females, have decreased body fat, moderate hypoglyce...
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MDPI AG
2024-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/9/1160 |
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| author | Alexandra V. Schmidt Sivakama S. Bharathi Keaton J. Solo Joanna Bons Jacob P. Rose Birgit Schilling Eric S. Goetzman |
| author_facet | Alexandra V. Schmidt Sivakama S. Bharathi Keaton J. Solo Joanna Bons Jacob P. Rose Birgit Schilling Eric S. Goetzman |
| author_sort | Alexandra V. Schmidt |
| collection | DOAJ |
| description | 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 <i>Sirt2−/−</i> 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 <i>Sirt2−/−</i> 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 <i>Sirt2−/−</i> male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in <i>Sirt2−/−</i> 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. |
| format | Article |
| id | doaj-art-313e585950c041e8a1492b3a783497cc |
| institution | OA Journals |
| issn | 2218-273X |
| language | English |
| publishDate | 2024-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-313e585950c041e8a1492b3a783497cc2025-08-20T01:56:05ZengMDPI AGBiomolecules2218-273X2024-09-01149116010.3390/biom14091160Sirt2 Regulates Liver Metabolism in a Sex-Specific MannerAlexandra V. Schmidt0Sivakama S. Bharathi1Keaton J. Solo2Joanna Bons3Jacob P. Rose4Birgit Schilling5Eric S. Goetzman6Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USAThe Buck Institute for Research on Aging, Novato, CA 94945, USAThe Buck Institute for Research on Aging, Novato, CA 94945, USAThe Buck Institute for Research on Aging, Novato, CA 94945, USADepartment of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USASirtuin-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 <i>Sirt2−/−</i> 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 <i>Sirt2−/−</i> 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 <i>Sirt2−/−</i> male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in <i>Sirt2−/−</i> 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.https://www.mdpi.com/2218-273X/14/9/1160sirtuinsirt-2liverglucosemetabolismgluconeogenesis |
| spellingShingle | Alexandra V. Schmidt Sivakama S. Bharathi Keaton J. Solo Joanna Bons Jacob P. Rose Birgit Schilling Eric S. Goetzman Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner Biomolecules sirtuin sirt-2 liver glucose metabolism gluconeogenesis |
| title | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner |
| title_full | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner |
| title_fullStr | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner |
| title_full_unstemmed | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner |
| title_short | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner |
| title_sort | sirt2 regulates liver metabolism in a sex specific manner |
| topic | sirtuin sirt-2 liver glucose metabolism gluconeogenesis |
| url | https://www.mdpi.com/2218-273X/14/9/1160 |
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