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Hepcidin production is increased in response to an increase in systemic iron via the activation of the bone morphogenetic protein (BMP) pathway. Regulation of hepcidin expression by iron status has been proposed on the basis of evidence mainly from rodents and humans. We evaluated the effect of iron administration on plasma hepcidin concentrations in calves and the expression of bovine hepcidin by the BMP pathway in a cell culture study. Hematocrit as well as levels of blood hemoglobin and plasma iron were lower than the reference level in calves aged 1\u20134\u2009weeks. Although intramuscular administration of iron increased iron\u2010related parameters, plasma hepcidin concentrations were unaffected. Treatment with BMP6 increased hepcidin expression in human liver\u2010derived cells but not in bovine liver\u2010derived cells. A luciferase\u2010based reporter assay revealed that Smad4 was required for hepcidin reporter transcription induced by Smad1. The reporter activity of hepcidin was lower in the cells transfected with bovine Smad4 than in those transfected with murine Smad4. The lower expression levels of bovine Smad4 were responsible for the lower activity of the hepcidin reporter, which might be due to the instability of bovine Smad4 mRNA. In fact, the endogenous Smad4 protein levels were lower in bovine cells than in human and murine cells. Smad4 also confers TGF\u2010\u03b2\/activin\u2010mediated signaling. Induction of TGF\u2010\u03b2\u2010responsive genes was also lower after treatment with TGF\u2010\u03b21 in bovine hepatocytes than in human hepatoma cells. We revealed the unique regulation of bovine hepcidin expression and the characteristic TGF\u2010\u03b2 family signaling mediated by bovine Smad4. The present study suggests that knowledge of the regulatory expression of hepcidin as well as TGF\u2010\u03b2 family signaling obtained in murine and human cells is not always applicable to bovine cells.<\/jats:p>","DOI":"10.1096\/fj.202301186rr","type":"journal-article","created":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T01:06:12Z","timestamp":1696640772000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Weak response of bovine hepcidin induction to iron through decreased expression of Smad4"],"prefix":"10.1096","volume":"37","author":[{"given":"Hiroyuki","family":"Sadakane","sequence":"first","affiliation":[{"name":"Division of Applied Biosciences, Graduate School of Agriculture Kyoto University  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Division of Applied Biosciences, Graduate School of 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