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

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

Author information

1
Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province 310053, China.
2
Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang Province 310007, China.
3
Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province 310053, China. Electronic address: geweihong@hotmail.com.

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

PMID:
28419832
DOI:
10.1016/j.toxlet.2017.04.009
[Indexed for MEDLINE]

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