| First Author | Lichten LA | Year | 2009 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 296 |
| Issue | 4 | Pages | G860-7 |
| PubMed ID | 19179618 | Mgi Jnum | J:149697 |
| Mgi Id | MGI:3848875 | Doi | 10.1152/ajpgi.90676.2008 |
| Citation | Lichten LA, et al. (2009) Interleukin-1beta contributes via nitric oxide to the upregulation and functional activity of the zinc transporter Zip14 (Slc39a14) in murine hepatocytes. Am J Physiol Gastrointest Liver Physiol 296(4):G860-7 |
| abstractText | Zinc metabolism during chronic disease is dysregulated by inflammatory cytokines. Experiments with IL-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 nitric oxide (NO) 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 S-nitroso N-acetyl penicillamine (SNAP). 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 activator protein (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 IL-1beta, an LPS-induced proinflammatory cytokine and a potent activator of inducible NO synthase (iNOS) and NO production. In support of our hypothesis, IL-1beta treatment led to a threefold 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 NO are factors in the upregulation of Zip14, which in turn mediates hepatic zinc accumulation and hypozincemia during inflammation and sepsis. |
