Academic Journal
Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.
| Τίτλος: | Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner. |
|---|---|
| Συγγραφείς: | Schmidt AV; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Bharathi SS; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Solo KJ; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Bons J; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Rose JP; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Schilling B; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Goetzman ES; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA. |
| Πηγή: | Biomolecules [Biomolecules] 2024 Sep 15; Vol. 14 (9). Date of Electronic Publication: 2024 Sep 15. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, 2011- |
| Ιατρικοί όροι (MeSH): | Sirtuin 2*/metabolism , Sirtuin 2*/genetics , Liver*/metabolism, Hepatocytes/metabolism ; Glucose/metabolism ; Gluconeogenesis/genetics ; Male ; Animals ; Female ; Mice ; Mice, Knockout ; Acetylation ; Mice, Inbred C57BL ; Sex Characteristics ; Glycolysis ; Sex Factors |
| Περίληψη: | 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. |
| References: | Nature. 2010 Mar 4;464(7285):121-5. (PMID: 20203611) Life Sci. 2022 Jul 15;301:120636. (PMID: 35568227) Genome Biol. 2004;5(5):224. (PMID: 15128440) Cell Div. 2018 Nov 10;13:9. (PMID: 30459823) World J Gastroenterol. 2014 Jan 7;20(1):22-30. (PMID: 24415854) Hum Mol Genet. 2017 Nov 1;26(21):4105-4117. (PMID: 28973648) Mol Cell Proteomics. 2017 Dec;16(12):2296-2309. (PMID: 29070702) Proteomics. 2023 Feb;23(3-4):e2100371. (PMID: 36479818) NPJ Aging Mech Dis. 2016 Aug 18;2:16017. (PMID: 28721271) Cancer Cell. 2013 Apr 15;23(4):464-76. (PMID: 23523103) Future Med Chem. 2013 Oct;5(16):1967-91. (PMID: 24175747) Antioxid Redox Signal. 2017 May 20;26(15):849-863. (PMID: 27460777) Hepatology. 2021 Aug;74(2):723-740. (PMID: 33636024) Sci Rep. 2017 Dec;7(1):7. (PMID: 28127057) DNA Repair (Amst). 2014 Nov;23:33-8. (PMID: 24814981) Nat Commun. 2017 Aug 21;8(1):291. (PMID: 28827567) Int J Mol Sci. 2019 Mar 18;20(6):. (PMID: 30889926) Biomolecules. 2015 Jun 29;5(3):1319-38. (PMID: 26131977) Front Oncol. 2020 Sep 08;10:1721. (PMID: 33014852) Biochemistry. 2015 May 19;54(19):3037-3050. (PMID: 25897714) Mol Cell Biol. 2003 May;23(9):3173-85. (PMID: 12697818) Mol Cell Proteomics. 2012 Jun;11(6):O111.016717. (PMID: 22261725) PeerJ. 2020 Jan 6;8:e8328. (PMID: 31934509) Genes Dev. 2006 May 15;20(10):1256-61. (PMID: 16648462) Cell Rep. 2021 Dec 28;37(13):110155. (PMID: 34965411) J Clin Invest. 2024 Apr 30;:. (PMID: 38687608) Cancer Cell. 2011 Oct 18;20(4):487-99. (PMID: 22014574) Physiol Rep. 2022 Feb;10(3):e15174. (PMID: 35133078) PLoS One. 2007 Aug 29;2(8):e784. (PMID: 17726514) PLoS One. 2018 Dec 11;13(12):e0208634. (PMID: 30533032) Redox Biol. 2019 Sep;26:101253. (PMID: 31234015) Mol Biol Cell. 2014 Jun 15;25(12):1854-66. (PMID: 24743598) Mol Cell. 2011 Jul 8;43(1):33-44. (PMID: 21726808) Diabetes Res. 1986 Feb;3(2):83-6. (PMID: 3698484) |
| Grant Information: | 5TL1DK132770-04A1 United States NH NIH HHS; 5S10AG028654-01A1 United States NH NIH HHS; 5R01HD103602-04A1 United States NH NIH HHS; S10 OD028654 United States OD NIH HHS; TL1 DK132770 United States DK NIDDK NIH HHS; R01 DK090242 United States DK NIDDK NIH HHS; 2P30DK120531-06A1 United States NH NIH HHS; 5R01DK090242-14A1 United States NH NIH HHS |
| Contributed Indexing: | Keywords: gluconeogenesis; glucose; liver; metabolism; sirt-2; sirtuin |
| Substance Nomenclature: | EC 3.5.1.- (Sirtuin 2) EC 3.5.1.- (Sirt2 protein, mouse) IY9XDZ35W2 (Glucose) |
| Entry Date(s): | Date Created: 20240928 Date Completed: 20240928 Latest Revision: 20260407 |
| Update Code: | 20260407 |
| PubMed Central ID: | PMC11430619 |
| DOI: | 10.3390/biom14091160 |
| PMID: | 39334926 |
| Βάση Δεδομένων: | MEDLINE |
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