title: A sexual dimorphism influences bicyclol-induced hepatic heat shock factor 1 activation and hepatoprotection.
abstract: Bicyclol [4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxy-methyl-2'-methoxycarbonyl biphenyl] is a synthetic hepatoprotectant widely used in clinical practice, but resistance to this treatment is often observed. We found that the hepatoprotective effect of bicyclol was greatly compromised in female and castrated male mice. This study was to dissect the molecular basis behind the sex difference, which might underlie the clinical uncertainty. We compared bicyclol-induced hepatoprotection between male and female mice using acute liver damage models. Inducible knockout by the Cre/loxp system was used to decipher the role of heat shock transcription factor 1 (HSF1). Functional experiments, western blot, and histopathological analysis were used to determine the key causative factors which might antagonize bicyclol in female livers. HSF1 activation and heat shock protein 70 (Hsp70) expression, which were responsible for bicyclol-induced hepatoprotection, were compromised in female and castrated male livers. Compromised HSF1 activation was a result of HSF1 phosphorylation at serine 303, which was catalyzed by glycogen synthase kinase 3β (GSK3β). Testosterone was necessary for bicyclol to inhibit hepatic GSK3β activity. Administration of testosterone or GSK3β inhibitors restored bicyclol-induced protection in females. Bicyclol induces sex-specific hepatoprotection based on a sex-specific HSF1/Hsp70 response, in which testosterone and GSK3β play key roles. Because a lot of patients suffering from liver diseases have very low testosterone levels, our results give a possible explanation for the clinical variation in bicyclol-induced hepatoprotection, as well as practicable solutions to improve the effect of bicyclol.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Conghui
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Huijuan
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Xianming
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Longmei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.) zhangming1973@yeah.net zhangjianjun@medmail.com.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital (X.C., Jianjian Z., H.D., X.K., Q.X., M.Z., Jianjun Z.), and The Central Laboratory of Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (L.X.); and Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China (C.H.) zhangming1973@yeah.net zhangjianjun@medmail.com.cn.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010766:Phosphorylation; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D013739:Testosterone; C477843:bicyclol; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3