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4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice

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Abstract

Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis, liver cancer, and related mortality. The endocannabinoid system contributes to the development of chronic liver diseases, where cannabinoid receptor 2 (CB2) has been shown to have a protecting role. Thus, here, we investigated how CB2 agonism by 4′-O-methylhonokiol (MHK), a biphenyl from Magnolia grandiflora, affects chronic alcohol-induced liver fibrosis and damage in mice. A combination of alcohol (10% vol/vol) and CCl4 (1 ml/kg) was applied to C57BL/6 mice for 5 weeks. MHK (5 mg/kg) was administered daily, and liver damage assessed by serum AST and ALT levels, histology, gene, and protein expression. Endocannabinoids (ECs) and related lipid derivatives were measured by liquid chromatography and mass spectrometry (LC-MS) in liver tissues. In vitro, MHK was studied in TGFβ1-activated hepatic stellate cells (HSC). MHK treatment alleviated hepatic fibrosis, paralleled by induced expression of matrix metalloproteinases (MMP)-2, -3, -9, and -13, and downregulation of CB1 mRNA. Necrotic lesions and hepatic inflammation were moderately improved, while IL-10 mRNA increased and IFNγ, Mcl-1, JNK1, and RIPK1 normalized by MHK. Hepatic anandamide (AEA) and related N-acetylethanolamines (NAEs) were elevated in MHK group, whereas fatty acid synthase and diacylglycerol O-acyltransferase 2 expression reduced. In vitro, MHK prevented HSC activation and induced apoptosis via induction of bak1 and bcl-2. To conclude, MHK revealed hepatoprotective effects during alcohol-induced liver damage through the induction of MMPs, AEA, and NAEs and prevention of HSC activation, indicating MHK as a potent therapeutic for liver fibrosis and ALD.

Key Messages

  • Methylhonokiol improves liver damage and survival.

  • Methylhonokiol reduces hepatic fibrosis and necroinflammation.

  • Methylhonokiol prevents myofibroblast activation and induces apoptosis.

  • Methylhonokiol upregulates endocannabinoids and related N-acylethanolamines.

  • Methylhonokiol contributes to lipid hydrolysis via PPARα/γ.

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Acknowledgments

We would like to thank Philip Kellmann (Department of Clinical Research, Hepatology, University of Bern, Switzerland) for the excellent technical assistance and high performance in the in vivo part of the study. The study was funded by a grant from the Swiss Foundation for Alcohol Research to E.P.

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Author notes

  1. Nasser Semmo and Felix Stickel share equal contribution

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, University Hospital Zürich, Sternwartstr. 14, 8097, Zurich, Switzerland

    Eleonora Patsenker & Felix Stickel

  2. Department of Clinical Research, Department of Hepatology, University of Bern, Bern, Switzerland

    Eleonora Patsenker, Sheida Moghadamrad, Andrea de Gottardi & Nasser Semmo

  3. Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

    Andrea Chicca, Vanessa Petrucci & Jürg Gertsch

  4. Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital, University Hospital of Bern, Bern, Switzerland

    Andrea de Gottardi & Nasser Semmo

  5. Medical Department 1, University Hospital Dresden, Technical University of Dresden, Dresden, Germany

    Jochen Hampe

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  1. Eleonora Patsenker
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  2. Andrea Chicca
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Correspondence to Eleonora Patsenker.

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Animal experiments and all experimental protocols were approved by the research animal ethics committee and by the local board on animal care and experimentation of Canton Bern and were performed according to international guidelines concerning the conduct of animal experimentation.

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The authors declare that they have no conflict of interests.

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Patsenker, E., Chicca, A., Petrucci, V. et al. 4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice. J Mol Med 95, 1077–1089 (2017). https://doi.org/10.1007/s00109-017-1556-y

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  • DOI: https://doi.org/10.1007/s00109-017-1556-y

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