HAMP - Hepcidin | Elisa - Clia - Antibody - Protein

Background:

Hepcidin, a peptide hormone primarily synthesized in the liver, plays a crucial role in regulating iron metabolism. It runs iron absorption in the intestine, release from macrophages, and transportation in the bloodstream by interacting with ferroportin, a protein responsible for exporting iron from cells. When hepcidin binds to ferroportin, it prompts internalization and degradation of ferroportin, ultimately reducing iron absorption and release into the bloodstream to maintain iron homeostasis. Various factors influence hepcidin synthesis and secretion, including iron stores, inflammation (as hepcidin is an acute phase reactant), hypoxia, and erythropoiesis. For instance, large iron stores induce the production of Bone Morphogenic Protein (BMP), which triggers hepcidin expression via the SMAD pathway. Inflammation stimulates hepcidin production by releasing interleukin-6, which activates the HAMP gene through the JAK/STAT pathway. Conversely, hypoxia suppresses hepcidin production through the action of hypoxia-inducible factor (HIF), which, under normal conditions, is degraded by von Hippel-Lindau (VHL) and prolyl dehydrogenase (PHD). Dysregulation of hepcidin levels can lead to disorders such as iron deficiency anemia or hereditary hemochromatosis.

Protein Structure:

Hepcidin is a small peptide hormone consisting of 25 amino acids in its mature form. It is initially synthesized as an 84-amino acid preprohepcidin, which undergoes proteolytic cleavage to produce prohepcidin (60 amino acids) and eventually the mature hepcidin-25. The structure of hepcidin is stabilized by four disulfide bonds, giving it a robust conformation essential for its biological activity.

Classification and Subtypes:

There are three main forms of hepcidin found in human serum: hepcidin-25, hepcidin-22, and hepcidin-20. Hepcidin-25 is the biologically active form, while the shorter forms (hepcidin-22 and hepcidin-20) are considered to be degradation products with reduced or no biological activity.

Function and Biological Significance:

• Iron Homeostasis: Hepcidin regulates iron levels by binding to the iron export protein ferroportin, which is located on the surface of enterocytes (intestinal cells), hepatocytes (liver cells), and macrophages (iron-storing cells). Upon binding, hepcidin induces the internalization and degradation of ferroportin, thereby reducing iron efflux into the bloodstream.
• Iron Absorption: By downregulating ferroportin, hepcidin decreases iron absorption from the diet. This mechanism is crucial during conditions of iron overload to prevent excessive accumulation of iron in the body.
• Iron Recycling: Hepcidin also controls the release of iron from macrophages, which recycle iron from senescent red blood cells. This process ensures a steady supply of iron for erythropoiesis (red blood cell production).
• Inflammation and Immunity: Hepcidin levels increase in response to inflammation and infection, a process mediated by cytokines such as interleukin-6 (IL-6). This increase helps to limit the availability of iron to pathogens, which require iron for growth, thus playing a role in the body's innate immune response.

Interactions:

• Ferroportin: The primary target of hepcidin is ferroportin, the sole known iron exporter in mammals. The interaction between hepcidin and ferroportin is central to iron homeostasis.
• IL-6 and Other Cytokines: Inflammatory cytokines, particularly IL-6, stimulate the production of hepcidin. This interaction is part of the acute-phase response to infection and inflammation.
• Transferrin Receptor and HFE Protein: Hepcidin expression is also influenced by the body's iron status. Increased levels of transferrin-bound iron and interactions with the HFE protein modulate hepcidin synthesis.

Clinical Issues:

• Iron Overload Disorders: Conditions such as hereditary hemochromatosis are characterized by low hepcidin levels, leading to excessive iron absorption and accumulation in tissues, causing damage to organs such as the liver, heart, and pancreas.
• Anemia of Chronic Disease: In chronic inflammatory conditions, elevated hepcidin levels can lead to reduced iron availability for erythropoiesis, contributing to anemia. This condition is commonly seen in chronic infections, autoimmune diseases, and cancers.
• Iron Deficiency Anemia: Conversely, inadequate hepcidin production can lead to iron deficiency anemia, where there is insufficient iron for red blood cell production despite adequate dietary intake.

Summary:

Hepcidin, encoded by the HAMP gene, is a central regulator of iron metabolism, controlling iron absorption, distribution, and storage through its interaction with ferroportin. It plays a significant role in maintaining iron homeostasis and responding to inflammation. Dysregulation of hepcidin levels is implicated in various clinical conditions, including iron overload disorders, anemia of chronic disease, and iron deficiency anemia. Understanding hepcidin's function and regulation provides insights into therapeutic strategies for managing these iron-related disorders.