Regulation of Iron MetabolismHarnish and Hariom Yadav

NATIONAL AGRI FOOD BIOTECHNOLOGY INSTITUTE,MOHALIEmail: yadavhariom@gmail.com

OBJECTIVES

Processes involved in iron metabolism.

Role of HEPICIDIN.

Diseases caused by Hepicidin deficiency.

IRON METABOLISM

Dietary Iron:Iron is essential element and must beprecisely regulated.On the lumen side of small intestine iron is

reduced from its ferric form(Fe3+) to ferrous form(Fe2+).

Ferrous iron is then transported in enterocytes by DMT1(divalent metal transporter).

Iron can be either stored within the enterocyte as ferritin or it can be transferred across the basolateral membrane to the plasma by transport protein FERROPORTIN1 and MTP1.(Requires oxidation of Ferrous to Ferric by hephaestin.)

TRANSPORT PROTEINS

DMT1 (Divalent Metal Transporter 1)(Tranports from lumen into the enterocytes)

FERROPORTIN1(Transports from enterocytes to circulation)

QUESTION????

Who is playing the central role in IRON METABOLISM??

ANSWER

HEPICIDIN is the key regulator of iron in our body.

What is HEPICIDIN??

Is a peptide hormone which was first identified in human urine and plasma in 2000.

Its molecular weight is 25 Kda.Highly folded structure.Present in inactive form;prohepcidin(60aa)

and its active form is hepicidin(25aa).

HEPICIDN25 Amino acid disulfide peptide.

Hepicidin, Primary regulator

Increased expression of hepicidin leads toDecrease iron absorption and release.Mutation :HemochromatosisIncreased expression:Iron deficiencyHepicidin mRna expression is increased by

erythropoetin,hypoxia & inflammation.Also binds to ferroportin.

Ferroportin

The only cellular iron exporter in vertebrates.Present in macrophages,placenta and the

hepatocytes.

Mechanism of action of hepicidin

The major mechanism of hepicidin is THE REGULATION OF TRANSMEMBRANE IRON TRANSPORT.

It binds to FERROPORTIN ,forms hepicidin-ferroportin complex ,which is degraded in the lysosomes and iron is locked inside the cells(mainly enterocytes,hepatocytes and macrophages).

SO

• Hepcidin lowers iron absorption in the intestine ,lowers iron releasing from hepatocytes and macrophages

Serum iron is decreased.

Hepicidin RegulationSo when hepicidin levels are low ,iron exporting cells have abundant ferroportin and thus releases iron into plasma.When hepicidin concentration increases it binds to ferroportin and thus iron is retained in the cells.

Regulation of Hepicidin

Hypoxia/AnemiaInflammation

Regulation of Hepcidin synthesis by anemia and hypoxia

• Oxygen Hepcidin Uptake of diet iron Iron release from hepatocytes Iron release from macrophages

Regulation of Hepcidin synthesis by inflammation

Interleukin-6 Hepcidin

iron anemia of chronic disease.

Generally when iron level ,ROS(Reactive oxygen species) that leads to in thiobarbutyric acid activation of NF Kappa proteins activates IL-6 , hepicidin synthesis

Disease States

Hepcidin deficiency, physiological = Haemochromatosis

Hepcidin excess – anaemia of chronic disease

The role of Hepcidin in hereditary hemochromatosis

• Hereditary hemochromatosis:-excessive intestinal iron absorption-Saturation of transferrin-Iron deposition in vital organs

Overall summary

Hepcidin-Is a recently discovered liver produced 25

amino-acid peptide-Is a regulator of iron metabolism that controls

iron absorption and macrophage iron release.-Is regulated by erythropoietic needs( ) ,body

iron stores( ) and inflammation( )