1. 4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice
- Author
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Jochen Hampe, Andrea De Gottardi, Felix Stickel, Eleonora Patsenker, Nasser Semmo, Andrea Chicca, Jürg Gertsch, Vanessa Petrucci, Sheida Moghadamrad, University of Zurich, and Patsenker, Eleonora
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,2716 Genetics (clinical) ,Alcoholic liver disease ,Cirrhosis ,610 Medicine & health ,CCL4 ,Pharmacology ,Protective Agents ,Lignans ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Carbon Tetrachloride ,Liver Diseases, Alcoholic ,Genetics (clinical) ,Liver injury ,biology ,3002 Drug Discovery ,Biphenyl Compounds ,medicine.disease ,Mice, Inbred C57BL ,Fatty acid synthase ,10219 Clinic for Gastroenterology and Hepatology ,030104 developmental biology ,Liver ,Magnolia ,1313 Molecular Medicine ,Hepatic stellate cell ,biology.protein ,570 Life sciences ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Chemical and Drug Induced Liver Injury ,Hepatic fibrosis ,Liver cancer ,030217 neurology & neurosurgery ,Endocannabinoids - 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.
- Published
- 2017