title: Dysregulation of hepatic zinc transporters in a mouse model of alcoholic liver disease.
abstract: Zinc deficiency is a consistent phenomenon observed in patients with alcoholic liver disease, but the mechanisms have not been well defined. The objective of this study was to determine if alcohol alters hepatic zinc transporters in association with reduction of hepatic zinc levels and if oxidative stress mediates the alterations of zinc transporters. C57BL/6 mice were pair-fed with the Lieber-DeCarli control or ethanol diets for 2, 4, or 8 wk. Chronic alcohol exposure reduced hepatic zinc levels, but increased plasma and urine zinc levels, at all time points. Hepatic zinc finger proteins, peroxisome proliferator-activated receptor-α (PPAR-α) and hepatocyte nuclear factor 4α (HNF-4α), were downregulated in ethanol-fed mice. Four hepatic zinc transporter proteins showed significant alterations in ethanol-fed mice compared with the controls. ZIP5 and ZIP14 proteins were downregulated, while ZIP7 and ZnT7 proteins were upregulated, by ethanol exposure at all time points. Immunohistochemical staining demonstrated that chronic ethanol exposure upregulated cytochrome P-450 2E1 and caused 4-hydroxynonenal accumulation in the liver. For the in vitro study, murine FL-83B hepatocytes were treated with 5 μM 4-hydroxynonenal or 100 μM hydrogen peroxide for 72 h. The results from in vitro studies demonstrated that 4-hydroxynonenal treatment altered ZIP5 and ZIP7 protein abundance, and hydrogen peroxide treatment changed ZIP7, ZIP14, and ZnT7 protein abundance. These results suggest that chronic ethanol exposure alters hepatic zinc transporters via oxidative stress, which might account for ethanol-induced hepatic zinc deficiency.
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina;
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, Kentucky.
authors.forename: Jiayang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, Kentucky.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, Kentucky.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; and z_zhou@uncg.edu.
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D027682:Cation Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003677:Deficiency Diseases / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D027682:Cation Transport Proteins; D019392:Cytochrome P-450 CYP2E1; D051557:Hepatocyte Nuclear Factor 4; D006861:Hydrogen Peroxide; D047493:PPAR alpha; D015032:Zinc; C496593:Hnf4a protein, mouse; C500556:SLC39A14 protein, mouse; C494728:Slc39a5 protein, mouse; C000589478:Slc39a7 protein, mouse; C472293:ZnT7 protein, mouse; C027576:4-hydroxy-2-nonenal
keywords: alcoholic liver disease; oxidative stress; zinc; zinc transporters