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Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.

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Title: Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
Authors: Schmidt, Alexandra V., Bharathi, Sivakama S., Solo, Keaton J., Bons, Joanna, Rose, Jacob P., Schilling, Birgit, Goetzman, Eric S.
Source: Biomolecules (2218-273X); Sep2024, Vol. 14 Issue 9, p1160, 17p
Subject Terms: LIVER mitochondria, SIRTUINS, PROTEIN metabolism, GLUCOSE metabolism, FAT
Abstract: 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 Sirt2−/− 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 Sirt2−/− 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 Sirt2−/− male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2−/− 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. [ABSTRACT FROM AUTHOR]
Copyright of Biomolecules (2218-273X) is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Complementary Index
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  Label: Title
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  Data: Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
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  Data: <searchLink fieldCode="AR" term="%22Schmidt%2C+Alexandra+V%2E%22">Schmidt, Alexandra V.</searchLink><br /><searchLink fieldCode="AR" term="%22Bharathi%2C+Sivakama+S%2E%22">Bharathi, Sivakama S.</searchLink><br /><searchLink fieldCode="AR" term="%22Solo%2C+Keaton+J%2E%22">Solo, Keaton J.</searchLink><br /><searchLink fieldCode="AR" term="%22Bons%2C+Joanna%22">Bons, Joanna</searchLink><br /><searchLink fieldCode="AR" term="%22Rose%2C+Jacob+P%2E%22">Rose, Jacob P.</searchLink><br /><searchLink fieldCode="AR" term="%22Schilling%2C+Birgit%22">Schilling, Birgit</searchLink><br /><searchLink fieldCode="AR" term="%22Goetzman%2C+Eric+S%2E%22">Goetzman, Eric S.</searchLink>
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  Data: Biomolecules (2218-273X); Sep2024, Vol. 14 Issue 9, p1160, 17p
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22LIVER+mitochondria%22">LIVER mitochondria</searchLink><br /><searchLink fieldCode="DE" term="%22SIRTUINS%22">SIRTUINS</searchLink><br /><searchLink fieldCode="DE" term="%22PROTEIN+metabolism%22">PROTEIN metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22GLUCOSE+metabolism%22">GLUCOSE metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22FAT%22">FAT</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 Sirt2−/− 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 Sirt2−/− 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 Sirt2−/− male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2−/− 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. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Biomolecules (2218-273X) is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.3390/biom14091160
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 17
        StartPage: 1160
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      – SubjectFull: LIVER mitochondria
        Type: general
      – SubjectFull: SIRTUINS
        Type: general
      – SubjectFull: PROTEIN metabolism
        Type: general
      – SubjectFull: GLUCOSE metabolism
        Type: general
      – SubjectFull: FAT
        Type: general
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      – TitleFull: Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
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            NameFull: Schmidt, Alexandra V.
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            NameFull: Bharathi, Sivakama S.
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            – D: 01
              M: 09
              Text: Sep2024
              Type: published
              Y: 2024
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