A Sexual Dimorphism Influences Bicyclol-Induced Hepatic Heat Shock Factor 1 Activation and Hepatoprotection

Abstract

Bicyclol [4,6,59,69-bis(methylenedioxy)-2-hydroxymethyl-29-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 bicyclolinduced 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 3b (GSK3b). Testosterone was necessary for bicyclol to inhibit hepatic GSK3b activity. Administration of testosterone or GSK3b inhibitors restored bicyclol-induced protection in females. Bicyclol induces sex-specific hepatoprotection based on a sex-specific HSF1/Hsp70 response, in which testosterone and GSK3b 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.

Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB

“…33 The number of survival mice was counted and recorded every half an hour from 4 to 12 h after the GalN/LPS injection, then every 12 h till the seventh day after intoxication. No deaths were observed after the third day, so mice that survived over 72 h were considered to survive indefinitely.…”

“…33 In brief, nuclear extracts were isolated from the livers or cultured hepatocytes, using NE-PER Nuclear and Cytoplasmic Extraction Reagents (Product Number 78833, Pierce Biotechnology, Rockford, lL, USA), supplemented with Complete Protease Inhibitor Cocktail Tablets (Roche). Membranes containing nuclear protein fractions were blocked with LI-COR blocking buffer and were then incubated with rabbit primary antibodies against Sirt1 (1:1000; #2028, Cell Signaling Technology, Danvers, MA, USA), NF- κ B p65 (1:2000, #4764, Cell Signaling Technology), acetyl-NF- κ B p65 K310 (1:1000, #3045, Cell Signaling Technology), p53 (1:1000, ab131442, Abcam) and acetyl-p53 K379 (1:1000, #2570, Cell Signaling Technology).…”

Gender differences in trauma, shock and sepsis

“…Cytokine-mediated tissue inflammation is the first step in the development of sepsis and profound organ damage. Similar to other organ systems, there is also a gender dimorphic response to hepatic injury following trauma-hemorrhage [ 83 – 85 ].…”

The Immune Pathogenesis of Acute-On-Chronic Liver Failure and the Danger Hypothesis

“…It has been found that prostaglandin E1, a non-toxic HSP inducer, prevents ALF after large-scale hepatectomy by enhancing the production of HSP70 in residual liver (84). Bicyclic alcohol is a new type of hepatoprotective agent that induces the production of heat shock transcription factor 1 (HSF1) and promotes synthesis of HSP70 and the stress response, inducing sexspecific liver protection to prevent liver injury or failure (85). Dai et al found that bicyclol induces the overexpression of HSP27 in the liver, which significantly enhances the protection of an animal model of acute liver injury induced by Dgalactosamine/lipopolysaccharide (86).…”