The Action of JAK/STAT3 and BMP/HJV/SMAD Signaling Pathways on Hepcidin Suppression by Tucum-do-Cerrado in a Normal and Iron-Enriched Diets

Abstract

The Brazilian savanna fruit, tucum-do-cerrado (Bactris setosa Mart.) reduces hepatic hepcidin levels. Therefore, we investigated the effect of tucum-do-cerrado on the TfR/HFE and/or BMP/HJV/SMAD and JAK/STAT pathways, in normal and excess iron conditions. Rats were treated with: control diet (CT); control diet +15% tucum-do-cerrado (Tuc); iron-enriched diet (+Fe); or iron-enriched diet +15% tucum-do-cerrado (Tuc+Fe). Tucum-do-cerrado (Tuc) decreased hepatic Hamp and Hjv mRNA levels but did not alter Bmp6, Smad7, Tfr1, and Hfe mRNA levels; pSMAD1/5/8 and pSTAT3 protein levels; labile iron pool (LIP); and inflammatory biomarkers, compared to the CT group. The iron-enriched diet increased Hamp mRNA levels, as well as pSMAD1/5/8 and pSTAT3 protein levels, while no difference was observed in Hjv, Bmp6, Smad7, Tfr1, and Hfe mRNA levels and LIP compared to the CT group. The association of tucum-do-cerrado with the iron-enriched diet (Tuc+Fe) decreased Hamp, Hjv, Bmp6, and Hfe mRNA levels and pSTAT3 protein content compared to the +Fe group, while increased Hamp and decreased Hfe mRNA levels compared to the Tuc group. Therefore, the inhibition of hepatic hepcidin by tucum-do-cerrado consumption may involve the downregulation of intestinal Dmt1 and hepatic Hjv expression and deacetylation mediated by SIRT1 by a mechanism that is independent of tissue iron content. However, in excess iron conditions, the modulation of hepatic hepcidin expression by tucum-do-cerrado seems to be partially mediated by the inflammatory signaling pathway, as well as involves the chelating activity of tucum-do-cerrado.

Regulators of epigenetic change in ferroptosis‑associated cancer (Review)

“…Under iron overload, HAMP binds to FPN on target cell membranes and internalizes and degrades FPN in lysosomes, thereby inhibiting iron absorption by enterocytes and releasing iron from macrophages or hepatocytes into the serum, thus regulating iron absorption and distribution ( 17 ). At the molecular level, HAMP is regulated by the bone morphogenetic protein (BMP)/hemojuvelin (HJV)/SMAD signaling pathway ( 18 ). HJV is a co-receptor of BMP ( 19 ).…”