Hepcidin is the master regulator of iron homeostasis. In anaemia of chronic disease (ACD), hepcidin levels are INCREASED. What is the molecular mechanism by which elevated hepcidin causes hypoferraemia?
- A Hepcidin binds transferrin, reducing iron transport to erythroid precursors
- B Hepcidin upregulates DMT1 in enterocytes, increasing iron absorption but trapping it in enterocytes
- C Hepcidin binds ferroportin-1 on enterocytes, hepatocytes, and macrophages, causing its internalisation and degradation, trapping iron intracellularly ✓
- D Hepcidin inhibits erythropoietin synthesis in the kidney, reducing iron demand
Explanation
Hepcidin, a 25-amino-acid peptide produced by hepatocytes, binds to ferroportin-1 (the sole known iron export protein) on duodenal enterocytes, hepatocytes, and reticuloendothelial macrophages, causing ferroportin ubiquitination, internalisation, and lysosomal degradation. Without ferroportin, iron cannot be exported from these cells: iron absorbed by enterocytes is lost when cells are shed, and iron from RBC catabolism by macrophages is sequestered intracellularly. In ACD, IL-6 (from inflammation) stimulates hepatic hepcidin synthesis (via JAK-STAT3 and BMP6-SMAD pathways), causing iron restriction — an innate immune strategy to withhold iron from pathogens.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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