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Nitric oxide modulates intestinal Zip4 zinc transporter regulation during inflammation
Author(s) -
Liuzzi Juan P.,
Cousins Robert J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a720-c
Subject(s) - zinc deficiency (plant disorder) , nitric oxide , zinc , inflammation , chemistry , nitric oxide synthase , medicine , endocrinology , biology , organic chemistry
The up‐regulation of intestinal Zip4 seems to be critical for the adaptation to low zinc intake. Although the mechanism of Zip4 up‐regulation is still unclear, zinc deficiency is often accompanied by inflammation and increased intestinal iNOS expression. To investigate the role of iNOS and nitric oxide on the regulation of intestinal Zip4, experiments were carried out with mice and Caco‐2 cells. iNOS −/− mice were made zinc deficient by feeding them with a low zinc diet for two weeks. They were injected with either IL‐1α or saline and killed 12 h later. Zinc deficiency and cytokine treatment decreased serum zinc and induced diarrhea; however, these effects were exacerbated in iNOS −/− mice. Zinc deficiency increased intestinal iNOS expression nearly three fold. Intestinal Zip4 was up‐regulated by zinc deficiency in both genotypes and localized to the apical membrane. Interestingly, this effect was abolished in iNOS −/− mice when treated with IL‐1α. In Caco‐2 cells, treatment with the nitric oxide donor SNAP (4 h) or with the zinc chelator TPEN (48 h) caused Zip4 up‐regulation. These results suggest that iNOS expression is not essential for intestinal Zip4 up‐regulation caused by zinc deficiency; nevertheless, iNOS appears to be critical when there is an inflammatory process concomitant to the zinc deficiency. Finally, intestinal Zip4 expression seems to be up‐regulated by nitric oxide. Supported by NIH Grant DK31127 and Boston Family Endowment funds (RJC).