A Redox-resistant Sirtuin-1 Mutant Protects against Hepatic Metabolic and Oxidant Stress
| Autor: | Di Shao, David R. Pimentel, Jessica L. Fry, Markus Bachschmid, Richard A. Cohen, Reiko Matsui, Jingyan Han, Xiuyun Hou |
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| Rok vydání: | 2014 |
| Předmět: |
Male
endocrine system diseases Apoptosis medicine.disease_cause Biochemistry Mice chemistry.chemical_compound Sirtuin 1 Glutaredoxin Metabolic Syndrome chemistry.chemical_classification biology Liver Diseases Molecular Bases of Disease Hep G2 Cells Oxidants Glutathione Reactive Nitrogen Species Liver lipids (amino acids peptides and proteins) Oxidation-Reduction hormones hormone substitutes and hormone antagonists Signal Transduction Deacetylase activity animal structures Molecular Sequence Data Oxidative phosphorylation medicine Animals Humans Amino Acid Sequence Molecular Biology Glutaredoxins Reactive oxygen species Sequence Homology Amino Acid Cell Biology Molecular biology Mice Inbred C57BL Oxygen Oxidative Stress enzymes and coenzymes (carbohydrates) HEK293 Cells chemistry Mutation biology.protein Liver function Reactive Oxygen Species Oxidative stress |
| Zdroj: | Journal of Biological Chemistry. 289:7293-7306 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.520403 |
| Popis: | Sirtuin-1 (SirT1), a member of the NAD(+)-dependent class III histone deacetylase family, is inactivated in vitro by oxidation of critical cysteine thiols. In a model of metabolic syndrome, SirT1 activation attenuated apoptosis of hepatocytes and improved liver function including lipid metabolism. We show in SirT1-overexpressing HepG2 cells that oxidants (nitrosocysteine and hydrogen peroxide) or metabolic stress (high palmitate and high glucose) inactivated SirT1 by reversible oxidative post-translational modifications (OPTMs) on three cysteines. Mutating these oxidation-sensitive cysteines to serine preserved SirT1 activity and abolished reversible OPTMs. Overexpressed mutant SirT1 maintained deacetylase activity and attenuated proapoptotic signaling, whereas overexpressed wild type SirT1 was less protective in metabolically or oxidant-stressed cells. To prove that OPTMs of SirT1 are glutathione (GSH) adducts, glutaredoxin-1 was overexpressed to remove this modification. Glutaredoxin-1 overexpression maintained endogenous SirT1 activity and prevented proapoptotic signaling in metabolically stressed HepG2 cells. The in vivo significance of oxidative inactivation of SirT1 was investigated in livers of high fat diet-fed C57/B6J mice. SirT1 deacetylase activity was decreased in the absence of changes in SirT1 expression and associated with a marked increase in OPTMs. These results indicate that glutathione adducts on specific SirT1 thiols may be responsible for dysfunctional SirT1 associated with liver disease in metabolic syndrome. |
| Databáze: | OpenAIRE |
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