Dihydromyricetin modulates p62 and autophagy crosstalk with the Keap-1/Nrf2 pathway to alleviate ethanol-induced hepatic injury

Toxicol Lett. 2017 May 15;274:31-41. doi: 10.1016/j.toxlet.2017.04.009. Epub 2017 Apr 15.

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 150mg/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.

Keywords: Autophagy; Dihydromyricetin; Keap-1/Nrf2 pathway; Liver injury; p62.

MeSH terms

  • Animals
  • Autophagy
  • Biomarkers
  • Flavonols / administration & dosage
  • Flavonols / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Lipid Peroxidation
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Specific Pathogen-Free Organisms
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Biomarkers
  • Flavonols
  • Gtf2h1 protein, mouse
  • Interleukin-1beta
  • Interleukin-6
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Transcription Factors
  • dihydromyricetin