Format

Send to

Choose Destination
J Mol Med (Berl). 2017 Oct;95(10):1077-1089. doi: 10.1007/s00109-017-1556-y. Epub 2017 Jul 8.

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

Author information

1
Department of Gastroenterology and Hepatology, University Hospital Zürich, Sternwartstr. 14, 8097, Zurich, Switzerland. eleonora.patsenker@usz.ch.
2
Department of Clinical Research, Department of Hepatology, University of Bern, Bern, Switzerland. eleonora.patsenker@usz.ch.
3
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
4
Department of Clinical Research, Department of Hepatology, University of Bern, Bern, Switzerland.
5
Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital, University Hospital of Bern, Bern, Switzerland.
6
Medical Department 1, University Hospital Dresden, Technical University of Dresden, Dresden, Germany.
7
Department of Gastroenterology and Hepatology, University Hospital Zürich, Sternwartstr. 14, 8097, Zurich, Switzerland.

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.

KEYWORDS:

Alcohol; Cannabinoids; Liver; Methylhonokiol; Therapy

PMID:
28689299
DOI:
10.1007/s00109-017-1556-y
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Springer Icon for Zurich Open Access Repository and Archive
Loading ...
Support Center