Hepatic Overexpression of SIRT5 Deacylates Proteins in Multiple Metabolic Pathways to Ameliorate Metabolic Abnormalities and Attenuate Hepatic Steatosis in Ob/Ob Mice

Sirtuin 5 (SIRT5) is a NAD - dependent lysine deacylase. To investigate the potential role of SIRT5 and acylation in obesity and Type 2 Diabetes (T2D), we established and characterized the hepatic SIRT5 - overexpressing ob/ob mice (ob/ob - SIRT5 OE). The ob/ob - SIRT5 OE mice showed decreased malonylation and succinylation, improved cellular glycolysis, suppressed glyconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. A total of 955 malonylation sites on 434 proteins and 1,377 succinylation sites on 429 proteins were identified and quantitated. Further analysis revealed that malonylation was the major SIRT5 target in the glycolysis/gluconeogenesis pathway, while succinylation was the preferred SIRT5 target in the oxidative phosphorylation pathway. Our data suggested that hepatic overexpression of SIRT5 ameliorated the metabolic abnormalities of ob/ob mice, probably through demalonylating and desuccinylating proteins in the main met abolic pathways.Declaration of Interests: The authors declare no competing interests.Funding: This work was supported by the National Natural Science Foundation of China (31671175, 31771257, 61773025), the Strategic Priority Research Programs (Category A) of the Chinese Academy of Sciences (XDA12030207), the National Key R&D Program of China (2017YFA0205501), the interdisciplinary medicine Seed Fund of Peking University (BMU2017MB001) and the National Laboratory of Biomacromolecules.The study design was approved by the appropriate ethics review boards.