Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice

Abstract

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here, we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. While liver iron content is independently positively correlated with hepatic Bmp6 mRNA expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, while the hepatic Erk1/2 signaling pathway is not activated by iron in vivo.

Smad7 deficiency decreases iron and haemoglobin through hepcidin up‐regulation by multilayer compensatory mechanisms

“…The expression of Smad7 has been linked to dietary iron 19, 20, 30. We thus have been suggested that feeding Smad7 Alb/Alb mice with an iron‐rich diet might induce a more robust phenotype.…”

“…We thus have been suggested that feeding Smad7 Alb/Alb mice with an iron‐rich diet might induce a more robust phenotype. According to the report, the hepcidin level reached to its peak at the 3rd day of iron‐rich diet treatment 30. We therefore choose a 3‐day iron‐rich diet treatment for the following experiments.…”

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

“…On the other hand, most high fat diet models induce metabolic changes but not fibrosis [66,67] . Furthermore, introduction of iron in the diet can create secondary effects by up-regulating liver hepcidin synthesis and thereby inhibiting the expression of iron exporter, ferroportin [68][69][70] . This will then lead to sequestration of iron in Kupffer cells and trigger inflammation.…”

Anaemia of Chronic Kidney Disease: What We Know Now

“…Intracellular iron stores interact with hepcidin via the BMP6 pathway activating SMAD and increasing hepcidin levels. Circulating transferrin-bound iron exerts its effects via the haemochromatosis protein (HFE)/transferrin receptor 2 (TFR2) pathway (14,15). Mutations of these receptors are associated with hereditary haemochromatosis resulting in iron overload via dysregulated hepcidin expression (16,17).…”