Clinical Application Value of Hepcidin

Summary of Hepcidin

Hepcidin is a cysteine-rich antimicrobial polypeptide synthesized and secreted by the liver. It was first isolated and purified from human blood by Krause in 2000 and then by Park et al. In 2001 to study the antimicrobial properties of human fluids Urine separated and named Hepcidin. As with antibacterial peptides found in plants, insects and mollusks, human Hepcidin also has a wide range of antibacterial and antiprotozoal effects. Damage, infection and inflammatory stimulation can strongly increase the expression of Hepcidin gene, while Hepcidin itself may be an important downstream effector that affects the transport of iron between different iron pools.

Molecular Structure and Gene Structure of Hepcidin         

Hepcidin molecules are composed of 8 cysteine ​​residues to form a single hairpin structure with four disulfide bonds. The amino acid sequences are highly conserved in different mammals. Three Hepcidins, Hepcidin22, Hepcidin25 and Hepcidin20 Hepcidin25 and Hepcidin20 are three or five amino acids less than the N-terminus of Hepcidin25, and are thought to be a degradation product of Hepcidin25. Hepcidin25 and Hepcidin20 are more likely to be Hepcidin25 degradation products. CD spectroscopic studies have shown that Hepcidin has two stable β-fold structures in phosphate buffered saline. This structure is very similar to the cysteine ​​structure of the antimicrobial polypeptide and belongs to the defensin family and participates in the natural defense of the host.

The human Hepcidin gene is located on chromosome 19 with three exons and two introns, where the third exon encodes its amino acid sequence. Hepcidin gene upstream and upstream stimulating factor2, (USF2) gene is closely linked, there is only 1.24kb interval between the two, there is a transcription factor CAAT enhancer binding protein, nuclear factor κB and hepatocyte nuclear factor Binding site.

Expression and Regulation of Hepcidin in Iron Metabolism Process

Most of the body of iron from the aging of red blood cells by macrophage phagocytosis after the recovery of heme iron, the other part of the absorption of iron from the food, the small intestine is the only part of the absorption of iron, the stomach and Duodenal cytochromeb(Dcytb) first reduced Fe3 + in food to Fe2 + and then transported to small intestinal epithelial cells by divalent metal transporter 1 (DMT1), while hemoglobin (Heme) Cell absorption and degradation of the release of Fe2 +, the above channels to absorb the Fe2 + on the one hand in the form of Hepcidin stored in the liver, small intestine and macrophages for the body when needed. On the other hand, it was released into the blood through the intestinal epithelial cell base membrane under the combined action of ferroportin 1 (FPN1) and membrane hephaestin(Hp) and oxidized to Fe3+ Hepcidin (transferrin, Tf), transported in the form of Tf-Fe2, reaches the liver through the portal system, and the liver cells are ingested by these combined iron, mediated by transferrin receptor 2 (TfR2) Iron through the blood to the bone marrow for hemoglobin synthesis and erythropoiesis, or with the erythrocytes on the TfR1 into the reticulocytes for red blood cell differentiation process of hemoglobin synthesis, the final iron in the various tissues and organs and cells were used.

No matter what kind of biological, in the physiological state of the lack of excretion of iron mechanism, so the body’s iron stability depends on the key to the small intestine iron absorption and the balance between the body needs.

From the iron metabolism process, FPN1 is the only way to transport iron from cells to blood throughout the study. It has been found that Hepcidin binds to FPN1, promotes its internalization and degradation, and indirectly regulates iron homeostasis. When the body iron overload, Hepcidin gene expression increased, so that liver synthesis secretion of Hepcidin increased, thereby accelerating the degradation of FPN1, turn off the iron to the blood transport of exports, thereby reducing the small intestinal epithelial cells and macrophages transported to the blood of iron; When the body iron is lacking, the above process undergoes the opposite change, thus maintaining the iron steady state.

Expression and Regulation of Hepcidin in Immune Process

In recent years, studies have found that inflammation and other immune factors can lead to significant changes in iron metabolism, Hepcidin found to explain the immune response and the link between the iron metabolism provides a way. Hepcidin levels in the urine of inflammatory mice and laboratory-induced inflammatory responses were significantly elevated and Hepcidin mRNA levels were also significantly increased. At present, inflammation is mainly caused by IL-6 induced Hepcidin expression increased. In vitro and in vivo experiments, IL-6 was found to cause an increase in Hepcidin expression, whereas IL-6 knockout mice did not cause an increase in Hepcidin expression even if endotoxin was injected. In the immune response, IL-6 binds to IL-6 receptor alpha and activates JAKs (Janus kinase) to phosphorylate STAT proteins, especially STAT3. Phosphorylated STAT protein enters the nucleus and directly binds to the Hepcidin gene promoter to promote Hepcidin expression. Some scholars believe that IL-6 is through the SMAD4 to regulate Hepcidin expression, when it inhibited the liver cells in the SMAD4, it will no longer affect the expression of Hepcidin. Some scholars believe that the inflammatory response by NF-κB regulation of Hepcidin expression, in the rat Hepcidin gene also found NF-κB binding site. In addition, some scholars believe that macrophages and neutrophils increase the expression of Hepcidin by the production of TLR-4, but the specific regulation mechanism of Hepcidin in immune response is not clear.

Clinical Application Value of Hepcidin

Traditional treatments and drugs have never had a good effect on iron metabolic disorders, and Hepcidin acts as an iron-negative hormone that itself can become an exogenous drug that reduces iron levels in the body to treat iron overload disease. There are scholars at home and abroad found that supplementation of exogenous Hepcidin, hereditary hemochromatosis (Hred), iron-related neurodegenerative diseases and associated with iron deposition of chronic liver disease and other iron metabolism-related diseases, are different The degree of efficacy. In addition, the development of a Hepcidin inhibitor or Hepcidin blocker for the treatment of chronic inflammatory anemia by Hepcidin long-term overexpression caused by the disease is also very useful.