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.

Sandra Fernandes Arruda,Marcela De Sá Barreto Da Cunha,Natália Aboudib Campos Hankins,Larissa Valadares Ramos,Pedro Augusto Matos Rodrigues,Júlia Lima De Alencar Barbosa

doi:10.3390/nu12051515

Sandra Fernandes Arruda, Marcela De Sá Barreto Da Cunha + Show 4 more

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https://doi.org/10.3390/nu12051515

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Journal: Nutrients	Publication Date: May 22, 2020
Citations: 2	License type: CC BY 4.0

Affiliation: Universidade de Brasília

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.

Highlights

IntroductionSystemic iron homeostasis is finely regulated by the peptide hormone hepcidin, which is mainly synthesized by hepatocytes
Iron constitutes an essential element for several metabolic processes in the human organism; both iron deficiency and excess iron may be harmful and lead to iron metabolism disorders [1,2].Systemic iron homeostasis is finely regulated by the peptide hormone hepcidin, which is mainly synthesized by hepatocytes
Considering that the hepatic hemojuvelin expression may potentiate the expression of hepcidin signaled by the BMP6 pathway, acting as a BMP6 co-factor, we further investigated the levels of phosphorylated SMAD1/5/8

Summary

Introduction

Systemic iron homeostasis is finely regulated by the peptide hormone hepcidin, which is mainly synthesized by hepatocytes. Hepcidin inhibits duodenal iron absorption and iron release from. Hepatic hepcidin expression is modulated by hepatic and extracellular iron levels and by other stimuli such as proinflammatory response, erythropoiesis, or hypoxia [4]. High iron levels and a proinflammatory profile improve hepcidin expression, while erythropoiesis and hypoxia inhibit it. Transferrin receptor 1, transferrin receptor 2, and the human hemochromatosis protein (TFR1/TfR2/HFE), as well as the bone morphogenetic protein and hemojuvelin (BMP/HJV), constitute upstream regulatory proteins of two pathways that control hepcidin expression in response to circulating concentrations of transferrin bound iron (Tf-Fe2 ) and intracellular iron levels, respectively [3]. An increase in Tf-Fe2 levels displaces HFE from TfR1, which interacts with TfR2, and the Tf-Fe2 -HFE-TfR2 complex induces hepcidin transcription

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