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首页> 外文期刊>EBioMedicine >SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
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SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice

机译：SIRT5使代谢相关蛋白脱酰并减轻ob / ob小鼠的肝脂肪变性

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Background Sirtuin 5 (SIRT5) is a NAD+-dependent lysine deacylase. The SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. However, the biological role of SIRT5 and acylation in pathological states such as obesity and type 2 diabetes (T2D) remains elusive. Methods The hepatic SIRT5-overexpressing ob/ob mouse model (ob/ob-SIRT5 OE) was established by CRISPR/Cas9 gene editing tool Protein malonylation and succinylation lysine sites were identified by immunoprecipitation coupled lipid chromatography - tandem mass spectrometry (LC-MS/MS) methods. Findings The ob/ob-SIRT5 OE mice showed decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Bioinformatics analysis revealed that malonylation was the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation was the preferred SIRT5 target in the oxidative phosphorylation pathway. Interpretation Hepatic overexpression of SIRT5 ameliorated the metabolic abnormalities of ob/ob mice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders. Fund National Key R&D Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Programs (Category A) of the Chinese Academy of Sciences, the Interdisciplinary Medicine Seed Fund of Peking University and the National Laboratory of Biomacromolecules.
机译：背景Sirtuin 5（SIRT5）是NAD + 依赖的赖氨酸脱酰基酶。 SIRT5缺乏症小鼠模型表明，它在正常情况下对于代谢稳态是必不可少的。但是，SIRT5和酰化在诸如肥胖症和2型糖尿病（T2D）等病理状态下的生物学作用仍然难以捉摸。方法通过CRISPR / Cas9基因编辑工具建立肝SIRT5过表达的ob / ob小鼠模型（ob / ob-SIRT5 OE），通过免疫沉淀偶联脂质色谱-串联质谱法（LC-MS / MS）方法。结果ob / ob-SIRT5 OE小鼠显示出减少的丙二酰化和琥珀酰化，改善的细胞糖酵解，抑制的糖异生，增强的脂肪酸氧化和减弱的肝脂肪变性。鉴定并定量了434个蛋白质上的955个丙二酰化位点和429个蛋白质上的1377个琥珀酰化位点。生物信息学分析表明，丙二酰化是糖酵解/糖异生途径中主要的SIRT5靶标，而琥珀酰化是氧化磷酸化途径中的首选SIRT5靶标。解释SIRT5的肝过表达改善了ob / ob小鼠的代谢异常，可能是通过主要代谢途径中的去丙二酰化和去琥珀酰化蛋白来实现的。 SIRT5和相关的酰化作用可能是代谢障碍的潜在靶标。资助了中国国家重点研究开发计划，国家自然科学基金，中国科学院战略优先研究计划（A类），北京大学跨学科医学种子基金和生物大分子国家实验室。

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