Hepcidin
Encyclopedia
Hepcidin is a peptide hormone
produced by the liver
. It was discovered in 2000, and appears to be the master regulator of iron homeostasis
in humans and other mammal
s. In humans, HAMP
is the gene
that encodes for hepcidin.
Hepcidin is also a tightly folded polypeptide containing 25 residues in length and is 32% beta sheets. The 25 amino acids have a hairpin
structure
and are stabilized by 4 disulfide
bond
s, which has been shown to act as the principal regulator of iron homeostasis
in vertebrates. The structure of hepcidin has determined through the method of solution NMR
. The different NMR studies showed a new model for hepcidin. Revealing at ambient temperatures, interconverts between two different conformations, which could be individually resolved by temperature variation. Using the different methods, the solution structure of hepcidin was determined at 325 and 253 K in supercooled water. The hepcidin conformation had appeared to be stabilized when the X-ray analysis of a co-crystal with Fab study was completed. This is similar to the high-temperature NMR structure.
, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Inhibiting ferroportin shuts off the iron transport out of these cells, which store iron. By inhibiting ferroportin, hepcidin prevents enterocytes of the intestines from secreting iron into the hepatic portal system, thereby functionally reducing iron absorption. The iron release from macrophages is also prevented by ferroportin inhibition; therefore, the hepcidin maintains iron homeostasis. Hepcidin activity is also partially responsible for iron sequestration seen in anemia of chronic disease, and levels are elevated in people with renal failure
.
Several mutations in hepcidin result in juvenile hemochromatosis
. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin
, a regulator of hepcidin production.
Hepcidin has shown fairly consistent antifungal activity. Hepcidin's antibacterial activity currently seems to be inconsistent. The current scientific evidence suggests that hepcidin is a central regulatory hormone, and its main action is to regulate systemic iron homeostasis.
, researchers working in the lab of Tomas Ganz discovered a peptide associated with inflammation, and named it "hepcidin" after observing that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing"). Both groups were focused on the antimicrobial properties of the peptide.
Hepcidin was first discovered in human
urine
and serum
in 2000. Most understandings of hepcidin regulation and action comes from in vitro
and mice studies that often use hepcidin mRNA expression as a read-out. Carrying out studies in humans is difficult due to the lack of suitable hepcidin assay
. With the recent developments of assays to measure hepcidin in serum and urine, new opportunities to study the regulation of hepcidin in humans have arisen. Only a few laboratories are able to perform these assays at the current moment. The aim of the studies is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.
Soon after this discovery, researchers discovered that hepcidin production in mice
increases in conditions of iron overload as well as in inflammation. Genetically modified
mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting a central and not redundant role in iron regulation. The first evidence that linked hepcidin to the clinical condition known as the anemia of inflammation
came from the lab of Nancy Andrews in Boston when researchers looked at tissue from two patients with liver tumor
s with a severe microcytic anemia
that did not respond to iron supplementation. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidin mRNA
. Removing the tumors surgically cured the anemia.
Taken together, these discoveries suggested that hepcidin regulates the release of iron in the body.
levels decreases over time, while the concentration of iron in the liver
, spleen
, and kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. It was found that patients with β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis
and whether the concentration of hepcidin is increasing in the body of such patients might be therapeutic, limiting iron overload. It was demonstrated that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis
and splenomegaly
, and an increase in total hemoglobin
levels. The data led the researchers to suggest therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
produced by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. It was discovered in 2000, and appears to be the master regulator of iron homeostasis
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
in humans and other mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s. In humans, HAMP
HAMP
Hepcidin is a protein that in humans is encoded by the HAMP gene.The product encoded by this gene is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption...
is the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that encodes for hepcidin.
Structure
Hepcidin preprohormone, prohormone, and hormone size are 84, 60, and 25 amino acids, respectively. Twenty- and 22-amino acid forms of Hepcidin also exist in the urine. The N terminal region is required for function, and deletion of 5 N-terminal peptides results in a loss of function.Hepcidin is also a tightly folded polypeptide containing 25 residues in length and is 32% beta sheets. The 25 amino acids have a hairpin
Stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when read in opposite directions,...
structure
Structure
Structure is a fundamental, tangible or intangible notion referring to the recognition, observation, nature, and permanence of patterns and relationships of entities. This notion may itself be an object, such as a built structure, or an attribute, such as the structure of society...
and are stabilized by 4 disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
bond
Chemical bond
A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...
s, which has been shown to act as the principal regulator of iron homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
in vertebrates. The structure of hepcidin has determined through the method of solution NMR
Protein nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins. The field was pioneered by Richard R. Ernst and Kurt Wüthrich, among others...
. The different NMR studies showed a new model for hepcidin. Revealing at ambient temperatures, interconverts between two different conformations, which could be individually resolved by temperature variation. Using the different methods, the solution structure of hepcidin was determined at 325 and 253 K in supercooled water. The hepcidin conformation had appeared to be stabilized when the X-ray analysis of a co-crystal with Fab study was completed. This is similar to the high-temperature NMR structure.
Function
The 25-amino acid peptide of hepcidin is secreted by the liver, which seems to be the "master regulator" of iron metabolism. Hepcidin inhibits iron transport by binding to the iron channel ferroportinFerroportin
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:*Enterocytes in the duodenum*Hepatocytes...
, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Inhibiting ferroportin shuts off the iron transport out of these cells, which store iron. By inhibiting ferroportin, hepcidin prevents enterocytes of the intestines from secreting iron into the hepatic portal system, thereby functionally reducing iron absorption. The iron release from macrophages is also prevented by ferroportin inhibition; therefore, the hepcidin maintains iron homeostasis. Hepcidin activity is also partially responsible for iron sequestration seen in anemia of chronic disease, and levels are elevated in people with renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
.
Several mutations in hepcidin result in juvenile hemochromatosis
Juvenile hemochromatosis
Juvenile hemochromatosis is, as its name indicates, a form of hemochromatosis which emerges during youth.There are two forms:* "HFE2A" is associated with hemojuvelin...
. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin
Hemojuvelin
Hemojuvelin is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene...
, a regulator of hepcidin production.
Hepcidin has shown fairly consistent antifungal activity. Hepcidin's antibacterial activity currently seems to be inconsistent. The current scientific evidence suggests that hepcidin is a central regulatory hormone, and its main action is to regulate systemic iron homeostasis.
History
The peptide was initially reported as LEAP-1, for Liver-Expressed Antimicrobial Protein and later became known as hepcidin. Independently, in a search for antimicrobial peptidesAntimicrobial peptides
Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides...
, researchers working in the lab of Tomas Ganz discovered a peptide associated with inflammation, and named it "hepcidin" after observing that it was produced in the liver ("hep-") and appeared to have bactericidal properties ("-cide" for "killing"). Both groups were focused on the antimicrobial properties of the peptide.
Hepcidin was first discovered in human
Human
Humans are the only living species in the Homo genus...
urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
and serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
in 2000. Most understandings of hepcidin regulation and action comes from in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and mice studies that often use hepcidin mRNA expression as a read-out. Carrying out studies in humans is difficult due to the lack of suitable hepcidin assay
Assay
An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...
. With the recent developments of assays to measure hepcidin in serum and urine, new opportunities to study the regulation of hepcidin in humans have arisen. Only a few laboratories are able to perform these assays at the current moment. The aim of the studies is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.
Soon after this discovery, researchers discovered that hepcidin production in mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
increases in conditions of iron overload as well as in inflammation. Genetically modified
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
mice engineered to overexpress hepcidin died shortly after birth with severe iron deficiency, again suggesting a central and not redundant role in iron regulation. The first evidence that linked hepcidin to the clinical condition known as the anemia of inflammation
Anemia of chronic disease
Anemia of chronic disease, also referred to as anemia of inflammatory response is a form of anemia seen in chronic illness, e.g. from chronic infection, chronic immune activation, or malignancy...
came from the lab of Nancy Andrews in Boston when researchers looked at tissue from two patients with liver tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s with a severe microcytic anemia
Microcytic anemia
Microcytic anemia is a generic term for any type of anemia characterized by small red blood cells. The normal mean corpuscular volume is 76-100 fL, with smaller cells as macrocytic....
that did not respond to iron supplementation. The tumor tissue appeared to be overproducing hepcidin, and contained large quantities of hepcidin mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
. Removing the tumors surgically cured the anemia.
Taken together, these discoveries suggested that hepcidin regulates the release of iron in the body.
Clinical significance
Beta-thalassemia is one of the most common congenital anemias arising from partial or complete lack of β-globin synthesis. Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. The serial analyses of β-thalassemic mice indicate hemoglobinHemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
levels decreases over time, while the concentration of iron in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, and kidneys markedly increases. The overload of iron is associated with low levels of hepcidin. It was found that patients with β-thalassemia also have low hepcidin levels. The observations led researchers to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
and whether the concentration of hepcidin is increasing in the body of such patients might be therapeutic, limiting iron overload. It was demonstrated that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
and splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, and an increase in total hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
levels. The data led the researchers to suggest therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.