As a functional component of erythrocyte hemoglobin, iron is essential for oxygen delivery to all tissues in the body. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. ...During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure the adequate supply of iron to the bone marrow for red blood cell production. However, mounting evidence suggested that another factor may exert a similar function. We identified the hepatokine fibrinogen-like 1 (FGL1) as a previously undescribed suppressor of hepcidin that is induced in the liver in response to hypoxia during the recovery from anemia, and in thalassemic mice. We demonstrated that FGL1 is a potent suppressor of hepcidin in vitro and in vivo. Deletion of Fgl1 in mice results in higher hepcidin levels at baseline and after bleeding. FGL1 exerts its activity by directly binding to bone morphogenetic protein 6 (BMP6), thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription.
Introduction
The liver-produced hormone hepcidin regulates the body iron stores. Its expression is induced by iron and inflammatory cytokines but repressed by the erythroid regulator erythroferrone ...(ERFE) when erythropoietic activity intensifies during anemia. Although Erfe-deficient mice fail to appropriately suppress hepcidin during the first 24h following hemorrhage, these mice still recover from anemia with a few days delay suggesting that another mechanism compensates for the absence of ERFE. We therefore decided to study the kinetic of hepcidin during the recovery from anemia induced by bleeding in Erfe-deficient mice.
Material and methods
Six week-old C57BL/6 WT and Erfe-deficient mice were phlebotomized (500 μL) and analyzed 1, 2, 3, 4, 5 and 6 days after phlebotomy until full recovery.
Results
Liver hepcidin mRNA expression was suppressed 5-fold one to five days after phlebotomy in WT mice. In contrast with the sustained inhibition of hepcidin, serum ERFE concentration progressively decreased after 24 hours to reach its baseline at day 4. Interestingly, although hepcidin levels were unchanged after 24 hours, Erfe-deficient exhibited significantly reduced hepcidin levels after 48 hours. Hepcidin mRNA and protein levels were comparable to those of WT mice 2 to 5 days after phlebotomy. Interestingly, the repression of hepcidin occurred without any change in phosphorylation of the effectors Smadd1/5/8 and in hepatic expression of the BMP/SMAD target genes Atoh8, Smad7 and Id1. Similarly, mRNA expression of the proposed negative regulators of hepcidin Gdf15, Twsg1 and Gdf11 was not increased in the spleen and the bone marrow of phlebotomized mice compared to control mice. Finally, disruption of the erythroid compartment by irradiation or injection of carboplatin prevented the suppression of hepcidin in WT and Erfe-deficient mice.
Conclusion
An alternative mechanism regulates hepcidin independently of iron and ERFE during stress erythropoiesis. Our data suggest that a second yet unknown erythroid regulator of hepcidin may exist.
No relevant conflicts of interest to declare.
Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the
splicing factor gene. Patients with MDS with
mutations often ...accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative
transcript in patients with MDS with the
mutation. Induction of this
transcript in primary
-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an
gene mutation than in patients with
wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with
-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant
transcript that was restricted to
-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box ...warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.
Scope
Non‐alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, the metabolic and hepatic effects of dietary amino acid (AA) source is assessed in ...Western diet (WD)‐induced NAFLD in male and female mice.
Methods and results
The AA source is either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein‐based WD display glucose intolerance, fasting hyperglycemia, and insulin‐resistance and develop NAFLD associated with changes in hepatic gene expression and microbiota dysbiosis. In contrast, males fed the AA‐based WD show no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein‐based WD. Females are protected against WD‐induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source.
Conclusions
Free dietary AA intake prevents the unhealthy metabolic outcomes of a WD preferentially in male mice.
The replacement of casein by a free amino acid mixture (AA), mimicking its composition, in a western‐diet (WD) prevents body weight gain in both male and female mice. Dietary free amino acids in the WD prevent hepatic damage and associated liver gene expression changes only in males. Collectively, the data show that free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex‐specific manner that may involve the gut microbiota.
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