title: Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2.
abstract: Phosphoenolpyruvate carboxykinase 1 (PEPCK1) is the critical enzyme for gluconeogenesis and is linked with type II diabetes. Previous studies have found that SIRT2, a deacetylase, plays an important role in deacetylating PEPCK1 and little is known about the anti-diabetic activity of SIRT2 inhibitors. In this study, we investigated the anti-diabetic effects of sirtinol, a SIRT2 inhibitor, on cell gluconeogenesis in vivo and in vitro. Immunoblotting analysis revealed that sirtinol significantly decreased the protein level of PEPCK1, and was accompanied by the hyperacetylation of PEPCK1 as well as decreased glucose output in a dose-dependent manner. Furthermore, sirtinol exerted little impact on endogenous PEPCK1 levels in SIRT2-knockdown cells. The in vitro experiments further confirmed the in vivo data; sirtinol decreased liver PEPCK1 protein level and prevented pyruvate-induced blood glucose from increasing. Based on our results, the rate-limiting enzyme PEPCK1 is the primary target of sirtinol, and the inhibition of SIRT2 activity may play an important role in cell gluconeogenesis. Thus, SIRT2 may be a novel molecular target for diabetes therapy and may thus shed light on the underlying diabetes treatment mechanisms of sirtinol.
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.|Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yida
authors.identifier: 0000-0002-1173-1074
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Dorfman
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Yuyao
authors.initials: Y
authors.lastname: Yin
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China. jieliu@fudan.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China. zhaosm@fudan.edu.cn.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001786:Blood Glucose; D005943:Gluconeogenesis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009284:Naphthols / Q000494:pharmacology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009284:Naphthols; C439060:sirtinol; D056565:Sirtuin 2; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)