Chronic alcohol consumption retards lipophagy, which contributes to the pathogenesis of
liver steatosis. Lipophagy-related Rab7 has been presumed as a crucial regulator in the progression of alcohol
liver disease despite elusive mechanisms. More importantly, whether or not hepatoprotective
quercetin targets Rab7-associated lipophagy disorder is unknown. Herein,
alcoholic fatty liver induced by chronic-plus-single-binge
ethanol feeding to male C57BL/6J mice was manifested by hampering autophagosomes formation with lipid droplets and fusion with lysosomes compared with the normal control, which was normalized partially by
quercetin. The GST-RILP pulldown assay of Rab7 indicated an improved GTP-Rab7 as the
quercetin treatment for
ethanol-feeding mice. HepG2 cells transfected with
CYP2E1 showed similar lipophagy dysfunction when exposed to
ethanol, which was blocked when cells were transfected with siRNA-Rab7 in advance.
Ethanol-induced steatosis and autophagic flux disruption were aggravated by the Rab7-specific inhibitor
CID1067700 while alleviated by transfecting with the Rab7Wt plasmid, which was visualized by immunofluorescence co-localization analysis and mCherry-GFP-LC3 transfection. Furthermore, TBC1D5, a
Rab GTPase-activating
protein for the subsequent normal circulation of Rab7, was downregulated after alcohol administration but regained by
quercetin. Rab7 circulation retarded by
ethanol and corrected by
quercetin was further revealed by fluorescence recovery after photobleaching (FRAP). Altogether,
quercetin attenuates hepatic steatosis by normalizing
ethanol-imposed Rab7 turnover disorders and subsequent lipophagy disturbances, highlighting a novel mechanism and the promising prospect of
quercetin-like
phytochemicals against the crucial first hit from alcohol.