title: Hepatic FoxO1 acetylation is involved in oleanolic acid-induced memory of glycemic control: novel findings from Study 2.
abstract: Our recent study (referred as Study 1) showed that the triterpenoid oleanolic acid (OA) was able to produce a sustained correction of hyperglycemia beyond treatment period in type 2 diabetes (T2D) mice with liver as a responsible site. To follow up the previous observations, the present study (referred as Study 2) investigated the possible role of acetylation of FoxO1 and associated events in this therapeutic memory by characterizing the pathways regulating the acetylation status during and post-OA treatments. OA treatment (100 mg/kg/day for 4 weeks, during OA treatment) reduced hyperglycemia in T2D mice by ∼87% and this effect was largely (∼70%) maintained even 4 weeks after the cessation of OA administration (post-OA treatment). During OA treatment, the acetylation and phosphorylation of FoxO1 were markedly increased (1.5 to 2.5-fold) while G6Pase expression was suppressed by ∼80%. Consistent with this, OA treatment reversed pyruvate intolerance in high-fat fed mice. Histone acetyltransferase 1 (HAT1) content was increased (>50%) and histone deacetylases (HDACs) 4 and 5 (not HDAC1) were reduced by 30-50%. The OA-induced changes in FoxO1, G6Pase, HAT1 and HDACs persisted during the post-OA treatment period when the increased phosphorylation of AMPK, SIRT1 content and reduced liver triglyceride had subsided. These results confirmed the ability of OA to control hyperglycemia far beyond treatment period in T2D mice. Most importantly, in the present study we demonstrated acetylation of FoxO1 in the liver is involved in OA-induced memory for the control of hyperglycemia. Our novel findings suggest that acetylation of the key regulatory proteins of hepatic gluconeogenesis is a plausible mechanism by the triterpenoid to achieve a sustained glycemic control for T2D.
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Songpei
authors.initials: S
authors.lastname: Li
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Charlie C L
authors.initials: CC
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Molero
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009828:Oleanolic Acid; D051548:Histone Acetyltransferases; C110880:histone acetyltransferase type B complex; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1