title: APPL1-mediated activation of STAT3 contributes to inhibitory effect of adiponectin on hepatic gluconeogenesis.
abstract: Adiponectin has been shown to suppress hepatic gluconeogenesis. However, the signaling pathways underlying its action remain ill-defined. The purpose of this study was to examine the potential role of APPL1 in mediating anti-gluconeogenic ability of adiponectin. Primary hepatocytes were isolated from male C57BL/6 mice. Western blot and RT-PCR were performed to detect protein expression and mRNA level, respectively. The protein-protein association was determined by immunoprecipitation and GST pull-down assay. We found that APPL1 protein levels were negatively associated with expressions of proteins and mRNAs of gluconeogenesis enzymes under stimulation with adiponectin. In addition, adiponectin-stimulated STAT3 phosphorylation and acetylation were positively regulated by APPL1 and negative regulated by SirT1. Pharmacological and genetic inhibition of STAT3 mitigated impact of adiponectin on hepatic gluconeogenesis. Furthermore, adiponectin administration facilitated the binding of APPL1 to SirT1 and suppressed the association of SirT1 with STAT3. Taken together, our study showed that APPL1-SirT1-STAT3 pathway mediated adiponectin signaling in primary hepatocytes. This new finding provides a novel mechanism by which adiponectin suppresses hepatic gluconeogenesis.
authors.affiliation: Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan 430060, China.
authors.forename: Youming
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Deling
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan 430060, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan 430060, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan 430060, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China. Electronic address: chwang0525@whu.edu.cn.
authors.forename: Changhua
authors.initials: C
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D005943:Gluconeogenesis / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C510733:Appl1 protein, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: APPL1; Adiponectin; Gluconeogenesis; STAT3; SirT1