Emerging evidence has demonstrated that chronic
ethanol exposure induces
iron overload, enhancing
ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound
quercetin on
ethanol-induced
iron overload and liver damage, focusing on the signaling pathway of the
iron regulatory
hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing
ethanol (accounting for 30% of total calories) and/or carbonyl
iron (0.2%) and treated with quecertin (100 mg/kg
body weight) for 15 weeks. Mouse primary hepatocytes were incubated with
ethanol (100 mM) and
quercetin (100 μM) for 24 h. Mice exposed to either
ethanol or
iron presented significant fatty infiltration and
iron deposition in the liver; these symptoms were exacerbated in mice cotreated with
ethanol and
iron.
Quercetin attenuated the abnormity induced by
ethanol and/or
iron.
Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased
hepcidin expression. These effects were partially alleviated by
quercetin supplementation in mice and hepatocytes. Importantly,
ethanol caused suppression of SMAD4 binding to the HAMP promoter and of
hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by
quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with
iron and
ethanol, especially exposure of
iron alone, activated BMP6/SMAD4 pathway and up-regulated
hepcidin expression, which was also normalized by
quercetin in vivo.
Quercetin prevented
ethanol-induced hepatic
iron overload different from what carbonyl
iron diet elicited in the mechanism, by regulating
hepcidin expression via the BMP6/SMAD4 signaling pathway.