Zinc metabolism during chronic disease is dysregulated by inflammatory cytokines. Experiments with IL 6 (interleukin 6) knockout mice show that LPS regulates expression of the zinc transporter, Zip14, by a mechanism that is partially independent of IL 6. The LPS induced model of sepsis may occur by a mechanism signaled by NO (nitric oxide) as a secondary messenger. To address the hypothesis that NO can modulate Zip14 expression, we treated primary hepatocytes from wild type mice with the NO donor SNAP (s nitroso n acetyl penicillamine). After treatment with SNAP, steady state Zip14 mRNA levels displayed a maximal increase after 8 h, and a concomitant increase in the transcriptional activity of the gene. Chromatin immunoprecipitation documented the kinetics of AP 1 and RNA polymerase II association with the Zip14 promoter after NO exposure, indicating a role of AP 1 in transcription of Zip14. We then stimulated the primary murine hepatocytes with interleukin 1 (IL 1), an LPS induced proinflammatory cytokine and a potent activator of iNOS (inducible nitric oxide synthase) and nitric oxide production. In support of our hypothesis, IL 1 treatment led to a three fold increase in Zip14 mRNA and enhanced zinc transport, as measured with a zinc fluorophore, in wild type, but not iNOS^-/- hepatocytes. These data suggest that signaling pathways activated by nitric oxide are factors in the up regulation of Zip14 that in turn mediates hepatic zinc accumulation and hypozincemia during inflammation and sepsis.