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HAMP

MIM.606464

Tuesday 5 August 2008

Hepcidin, a 25-amino-acid peptide, is a central regulator of iron absorption.

Hepcidin mRNA is upregulated by iron overload and by the cytokines IL-1 and IL-6. It is downregulated by hypoxia.

Regulation of hepcidin by cytokines and by hypoxia is readily demonstrated in primary hepatocytes or in hepatocyte lines, but how iron excess stimulates hepcidin production in hepatocytes remains a mystery.

Incubating hepatocytes with iron does not increase transcription of hepcidin. Clearly, there must be a pathway from an iron sensor to hepcidin transcription, and this sensor and signaling pathway do not appear to be endogenous to the hepatocytes.

Neither is this pathway simply an interaction between macrophages and hepatocytes. Co-incubation of macrophages with hepatocytes does not stimulate hepcidin mRNA levels, either when iron is added to an incubating mixture or when the macrophages are derived from heavily iron-laden mice. It has been proposed that the sensor is transferrin receptor 2 (TFR2).

The cognate receptor for hepcidin has been shown to be ferroportin. Hepcidin binds ferroportin (FPN1 or SLC40A1) and causes it to be internalized and degraded.

Hepcidin (HAMP) is synthesized by hepatocytes in response to both inflammatory stimuli and iron overload.

Studies in transgenic mice indicate that it has a key role in down-regulating the intestinal absorption and placental transport of iron and the release of iron by macrophages.

HAMP has been hailed as "the iron-regulatory hormone," although the mechanisms underlying its effects are unclear.

Pathology

- HAMP germline mutations in juvenile hemochromatosis (hemochromatosis type 2A, HJV2A) (MIM.602390).

NB: Juvenile hemochromatosis (JH) is caused by mutation in the gene HJV encoding hemojuvelin (MIM.608374), which maps to chromosome 1q21, whereas in others it is caused by mutation in the gene encoding hepcidin antimicrobial peptide (HAMP) (MIM.606464), which maps to chromosome 19q13. The 2 forms of juvenile hemochromatosis (HFE2) are here designated HFE2A and HFE2B, respectively.