An essential role for Hjv in the iron-sensing pathway. (A) Model depicting the dietary iron-sensing pathway in wild-type and Hjv-mutant mice. In wild-type mice, green arrows indicate responses in the presence of high iron; red arrows show responses in the presence of low iron. Balanced regulation of this pathway adjusts iron levels to the needs of the healthy organism (follow green or red arrows from left to right). In Hjv-mutant mice, iron-sensing is defective due to the absence of Hjv (indicated by gray double line). Despite high iron, this leads to an essentially complete absence of hepcidin expression, iron overload, and hemochromatosis (green arrows in Hjv mutant). Fpn, ferroportin. (B) Model depicting the impact of acute inflammation on the iron-sensing pathway (blue arrows). Acute-phase cytokines IL-6 and TNF-α act to coordinately downregulate Hjv expression in the liver while simultaneously inducing hepcidin expression. The reduction of Hjv results in a blockade of the dietary iron-sensing pathway (indicated by blue double line). This mechanism efficiently suppresses the iron-sensing pathway during the inflammatory response, which results in a low iron serum concentration inhibiting pathogenic growth.