Insights on the role of the protein hemojuvelin in the maintenance of systemic iron homeostasis
Bibliographic record
Abstract
Iron is an essential nutrient, involved in a wide range of biochemical activities. However, its flexible coordination chemistry and favorable redox potential may render this element potentially toxic. Thus, tight and accurate regulation of iron absorption in humans is critical to prevent systemic excess or deficiency. This complex task is accomplished by hepcidin, a liver-derived peptide hormone that binds to the iron transporter ferroportin and promotes its degradation. This results in a decrease of the iron efflux from duodenal enterocytes, macrophages and hepatocytes into the blood stream. Severalmolecules, such as HFE, TfRs, BMP6 and HJV, are being implicated in the regulation of hepcidin expression. HJV is encoded by the HFE2 gene and functions as a BMP co-receptor, activating hepcidin expression through the BMP/SMAD pathway. It is predominantly expressed in the skeletal muscles and at lower levels in the heartand the liver. Furthermore, a putative muscle-derived soluble Hjv is supposed to circulate in the plasma. Humans bearing pathogenic mutations of the HfE2 gene develop juvenile hemochromatosis, a disease characterized by profound hepcidindeficiency and early-onset severe iron overload. Mouse models with ubiquitous disruption of the expression of HJV recapitulate the main features of the disease. Previous studies have proposed an essential role for HJV in iron sensing, however, the implicated mechanisms have not been elucidated thus far. In this work we study the function of HJV within the iron metabolism regulatory mechanisms. In chapter II we investigate the role of HJV, expressed in different tissues, in the maintenance of iron homeostasis. We generate two novelmouse models with targeted disruption of the expression of Hjv in liver hepatocytes or skeletal muscle cells and we analyze their phenotype. We show that hepatic HJV suffices to regulate the expression of hepcidin and to maintainsystemic iron homeostasis whereas skeletal muscle HJV is dispensable for systemic iron metabolism. Furthermore, we do not observe any significant iron regulatory function of a putative muscle-derived soluble Hjv.In chapter III we focus our interest on the role of hepatic HJV in iron sensing to hepcidin. To this end, we analyze the molecular responses of HJV-/- and HJV+/+ mice to dietary iron manipulations. We demonstrate that HJV is not essential for iron sensing and it rather functions as an enhancer of the primary iron signal. Furthermore, we provide evidence of iron-dependent regulation of duodenal DMT1 and tissue specific function of hepcidin in the spleen and the duodenum of the studied HJV-/- mice.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".