Dihydromyricetin modulates p62 and autophagy crosstalk with the Keap-1/Nrf2 pathway to alleviate ethanol-induced hepatic injury. (15th May 2017)

• Record Type: Journal Article
• Authors: Qiu, Ping; Dong, Yu; Li, Bo; Kang, Xian-jie; Gu, Chao; Zhu, Tao; Luo, Yun-yun; Pang, Min-xia; Du, Wei-feng; Ge, Wei-hong
• Is Part Of: Toxicology letters. Volume 274(2017)
• Page Start: 31
• Page End: 41
• Publication Date: 2017-05-15
• Subjects: ALD alcoholic liver disease -- ALP alkaline phosphatase -- ALT alanine aminotransferase -- ARE antioxidant response element -- AST aspartate aminotransferase -- CYP2E1 cytochrome P450, family 2, subfamily E, polypeptide 1 -- DAB 3, 3′-diaminobenzidine -- DAPI 4′, 6-diamidino-2-phenylindole, dihydrochloride -- DMY dihydromyricetin -- DTT dithiothreitol -- ECL enhanced chemiluminescence -- EDTA ethylene diamine tetraacetic acid -- EGTA ethylene glycol-bis(2-aminoethyl ether)-N, N, N′, N′-tetraacetic acid -- ELISA enzyme-linked immunosorbent assay -- GSH glutathiose -- H&E haematoxylin-eosin -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HO-1 haeme oxygenase 1 -- HPLC high performance liquid chromatography -- IgG immunoglobulin G -- IL-1β interleukin 1 beta -- IL-6 interleukin 6 -- Keap-1 kelch-like ECH-associated protein 1 -- LC3B light chain 3-beta -- LDH lactate dehydrogenase -- LPS lipopolysaccharide -- MDA malonydialdehyde -- NADPH nicotinamide adenine dinucleotide 2″-phosphate reduced tetrasodium salt -- NF-κB nuclear factor- κB -- Nrf2 erythroid 2-related factor 2 -- OCT opti-mum cutting temperature -- PBS phosphate buffer saline -- ROS reactive oxygen species -- RIPA radio-immunoprecipitation assay -- TBARS thiobarbituric acid reactive substances -- TEM transmission electron microscope; Dihydromyricetin -- Liver injury -- p62 -- Keap-1/Nrf2 pathway -- Autophagy; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2017.04.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Dihydromyricetin efficaciously protects against ethanol-induced liver damage. Dihydromyricetinpromotesp62-mediated Keap1 inactivation and Nrf2 activation. Dihydromyricetin inducessufficientautophagy to confirm p62-mediated Keap-1 degradation. Abstract: Increasing evidence has demonstrated that dihydromyricetin (DMY) contains highly effective antioxidative, anti-inflammatory, anti-microbial and anti-diabetic properties. Nevertheless, the underlying hepatoprotective mechanisms of DMY have infrequently been reported thus far. In the present study, C57BL/6 mice were fed with the Lieber-DeCarli diet containing alcohol or isocaloric maltose dextrin as a control diet with or without DMY (75 and 150 mg/kg/d bw) for 6 weeks. DMY significantly attenuated hepatic enzyme release, hepatic lipid peroxidation and triglyceride deposition induced by chronic alcohol exposure. In addition, DMY dramatically attenuated the alcohol-triggered elevation of the level of inflammatory cytokines and partially recovered hepatic pathological changes. Notably, DMY remarkably modified aberrant expression of CYP2E1, Keap-1 and HO-1 in the liver and simultaneously ameliorated disordered nuclear localization of NF-κB and Nrf2 to exert its hepatoprotective effects. Further mechanistic exploration suggested that DMY activated Nrf2, possibly mediated through the autophagy pathway. Analysis of the crosstalk among p62, Keap-1 and Nrf2 demonstrated that the p62 upregulation caused by DMY contributes to a positive feedback loop in Nrf2 activation. In summary, DMY likely modulates p62 and autophagy crosstalk with the Keap-1/Nrf2 pathway to alleviate liver steatosis and the inflammatory response in the pathological progression of ALD.