Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver

Kautz, Léon; Meynard, Delphine; Monnier, Annabelle; Darnaud, Valérie; Bouvet, R.; Wang, Rui-Hong; Deng, Chiuxia; Vaulont, Sophie; Mosser, Jean; Coppin, Hélène; Roth, Marie‐Paule

doi:10.1182/blood-2008-03-143354

Cited by 398 publications

(464 citation statements)

References 43 publications

(49 reference statements)

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“…In the liver, Hepcidin is transcriptionally regulated by Bmp6 (22,23) , and Id1 is a representative Bmp-responsive gene regulated at the transcription level (24) . Previous studies revealed that Fe overload up-regulated the expression of Bmp6 and Id1 in the liver (14,25) . Exogenous Bmp6 increased Hepcidin expression in Hep3B cells (22) as well as in the liver (23) .…”

Section: Resultsmentioning

confidence: 96%

“…Considering that hepatic Hepcidin transcription is triggered by excess Fe (13,14) , Mg deficiency is expected to increase Hepcidin expression in the liver; however, a previous study revealed an increase in the intestinal absorption of Fe in Mg-deficient rats (10) , suggesting the failure of regulatory Fe metabolism by Hepcidin. The present study examined the expression of hepatic Hepcidin in Mg-deficient rats.…”

Section: Abstract: Magnesium Deficiency: Hepcidin: Liver Iron Contenmentioning

confidence: 99%

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Hepcidin expression in the liver of rats fed a magnesium-deficient diet

et al. 2011

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Mg deficiency accelerates Fe accumulation in the liver, which may induce various metabolic disturbances. In the present study, we examined the gene expression of Hepcidin, a peptide hormone produced in the liver to regulate intestinal Fe absorption negatively, in Mgdeficient rats. Although liver Fe concentration was significantly higher in rats fed an Mg-deficient diet for 4 weeks than in rats fed a control diet, Hepcidin expression in the liver was comparable between the dietary groups. Previous studies revealed that Fe overload up-regulated Hepcidin expression through transcriptional activation by Fe-induced bone morphogenetic protein (Bmp) 6, a growth/differentiation factor belonging to the transforming growth factor-b family, in the liver. Mg deficiency up-regulated the expression of Bmp6 but did not affect the expression of inhibition of DNA binding 1, a sensitive Bmp-responsive gene. In addition, the expression of Bmp receptors such as activin receptor-like kinase 2 (Alk2), activin receptor type IIA (Actr2a), activin receptor type IIB (Actr2b) and Bmp type II receptor (Bmpr2) was lower in the liver of Mg-deficient rats than in that of control rats. The present study indicates that accumulation of hepatic Fe by Mg deficiency is a stimulant inducing Bmp6 expression but not Hepcidin expression by blunting Bmp signalling possibly resulting from down-regulation of the receptor expression. Unresponsive Hepcidin expression may have a role in Mg deficiency-induced changes related to increased liver Fe. Key words: Magnesium deficiency: Hepcidin: Liver iron content: Bone morphogenetic proteinMg is a cofactor of numerous enzymes and plays an essential role in a wide range of fundamental cellular reactions. Insufficient Mg intake therefore induces numerous abnormalities in rodents (1) . Mg deficiency induced oxidative stress, which was evaluated by lipid peroxidation, and apoptosis in rat liver (2,3) . In addition, TAG and total cholesterol concentrations were increased in the liver and serum of Mg-deficient rats (4) . These features resemble the altered metabolism in the liver of rats fed a high-Fe diet; Fe overload enhanced lipid peroxidation, increased apoptotic cell number and elevated liver fat concentration and serum lipid concentrations, including TAG and total cholesterol (5 -8) . In view of the accumulation of hepatic Fe in Mg-deficient rats (2,9,10) , increased hepatic Fe content may cause various Mg-deficiency-related abnormalities in the liver.Hepcidin was originally isolated from human urine as an anti-microbial peptide (11) and is currently recognised as a hormone secreted from the liver in response to the Fe overload; it negatively regulates intestinal Fe absorption through internalisation and degradation of an Fe transporter, ferroportin (12) . Considering that hepatic Hepcidin transcription is triggered by excess Fe (13,14) , Mg deficiency is expected to increase Hepcidin expression in the liver; however, a previous study revealed an increase in the intestinal absorption of Fe in Mg-deficient...

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Section: Resultsmentioning

confidence: 96%

Section: Abstract: Magnesium Deficiency: Hepcidin: Liver Iron Contenmentioning

confidence: 99%

Hepcidin expression in the liver of rats fed a magnesium-deficient diet

et al. 2011

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…Smad7 expression is up‐regulated in mice fed an iron‐rich diet and down‐regulated in mice fed an iron‐deficient diet 20. Given its role as a negative regulator of hepcidin, we have been suggested that deleting Smad7 would increase hepcidin's response to dietary iron.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

et al. 2018

J Cellular Molecular Medi

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To maintain iron homoeostasis, the iron regulatory hormone hepcidin is tightly controlled by BMP‐Smad signalling pathway, but the physiological role of Smad7 in hepcidin regulation remains elusive. We generated and characterized hepatocyte‐specific Smad7 knockout mice (Smad7 Alb/Alb), which showed decreased serum iron, tissue iron, haemoglobin concentration, up‐regulated hepcidin and increased phosphor‐Smad1/5/8 levels in both isolated primary hepatocytes and liver tissues. Increased levels of hepcidin lead to reduced expression of intestinal ferroportin and mild iron deficiency anaemia. Interestingly, we found no difference in hepcidin expression or phosphor‐Smad1/5/8 levels between iron‐challenged Smad7 Alb/Alb and Smad7 flox/flox, suggesting other factors assume the role of iron‐induced hepcidin regulation in Smad7 deletion. We performed RNA‐seq to identify differentially expressed genes in the liver. Significantly up‐regulated genes were then mapped to pathways, revealing TGF‐β signalling as one of the most relevant pathways, including the up‐regulated genes Smad6, Bambi and Fst (Follistatin). We found that Smad6 and Bambi—but not Follistatin—are controlled by the iron‐BMP–Smad pathway. Overexpressing Smad6, Bambi or Follistatin in cells significantly reduced hepcidin expression. Smad7 functions as a key regulator of iron homoeostasis by negatively controlling hepcidin expression, and Smad6 and Smad7 have non‐redundant roles. Smad6, Bambi and Follistatin serve as additional inhibitors of hepcidin in the liver.

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The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis

Rouault

Anderson

2009

The Liver

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Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver

Cited by 398 publications

References 43 publications

Hepcidin expression in the liver of rats fed a magnesium-deficient diet

Hepcidin expression in the liver of rats fed a magnesium-deficient diet

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

The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis

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