FIGURE 7.

Schematic diagram depicting the proposed role of miR-130a in BMP-SMAD signaling and hepcidin regulation under iron-deficient conditions. Under control conditions (left panel), BMP6 binds to the BMP type I receptor ALK2 or ALK3, the BMP type II receptor ACTRIIA, and the co-receptor HJV to induce phosphorylation of SMAD1/5/8 proteins, which complex with common mediator SMAD4 to increase transcription of hepcidin mRNA in hepatocytes. Hepcidin is secreted into the circulation to inhibit ferroportin (FPN) cell surface expression and decrease iron entry into the bloodstream. Under iron-deficient conditions (right panel), liver miR-130a expression is increased and targets the 3′UTR of ALK2 to inhibit expression. This acts in conjunction with a reduction in BMP6 mRNA expression and an increase in matriptase 2 (MTP2) protein expression (which is proposed to cleave HJV) to decrease signaling through the BMP-SMAD pathway, decrease hepcidin expression, increase ferroportin expression, and thereby increase iron availability.