Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS

Pathogenesis of liver damage by dietary iron and nutritional

Four main thematics have been developed:

- Characterization of hepcidin. The discovery of the link between hepcidin and iron metabolism, achieved by our Group just before the starting of the contract, represented a major breakthrough for the understanding of iron metabolism. Indeed, numerous other studies have since led to conclude that hepcidin is the key hormonal regulator of iron status in the body. During the contract period, we showed that hepcidin expression, at the transcriptional level : i) was modulated in mice by the genetic background including gender and sex, and in humans by hepatic function, hepatic iron concentration and haemoglobin levels ; ii) was well correlated in humans with the quantification of hepcidin in urine, therefore validating this urinary quantitative approach. However, our efforts for producing a specific anti-hepcidin antibody have not yet been successful.

- Regulation of the expression of hepatic genes, including iron metabolism genes, by body iron status. Using a home-made hepatic c-DNA chips (dedicated c-DNA microarray), we were able, in the original human HepaRG cell line, to associate iron storage capacity and hepatocyte differentiation. Through a macroarray approach, we have identified Cyclin D1 overexpression in the liver of iron overloaded mice ; in view of the parallel increase in liver mass, hepatocyte ploidy and mitotic index, this Cyclin D1 overexpression could induce or reflect an abnormal progression of hepatocytes in the cell cycle.

- Determination of abnormal iron species in various pathological groups of patients. Two main types of complementary data were obtained : i) the demonstration of the presence of non-transferrin bound iron (NTBI) in the plasma of untreated HFE hemochromatosis (once transferrin saturation is above 45%) and of alcoholic cirrhotic patients ; ii) the detection of labile plasma iron (LPI), a redox active component of non-transferrin bound iron, in untreated HFE hemochromatosis and in alcoholic cirrhosis, when transferrin saturation is over 75%.

- Use of new-iron trapping agents. We showed, in liver cell cultures, that the bidentate hydroxypyridinone CP411 and the hexadentate O-trensox were more efficient than CP20 for protecting iron-related hepatocyte toxicity and for inhibiting tumor cell proliferation. Studying the link between polyamines and iron, we demonstrated that :
-- Polyamine-iron complexes exhibit an active cellular uptake through the polyamine transport system, and

-- The high antiproliferative effect of both O-trensox and the new oral iron tridentate chelator ICL670 may be the consequence of both iron and polyamine depletion.

We think that these data fulfil our main objectives which were :
- To improve our understanding of the mechanisms accounting for liver iron excess and liver cell iron toxicity at the organ, cellular and molecular levels ;

- To define (or to pave the road for defining) new genetic and biochemical markers having a diagnostic or prognostic value in iron overloaded situations ;

- To define (or to pave the road for defining) a therapeutic approach based on the use of iron-trapping agents not only for counteracting the toxicity related to cellular iron excess but also for contributing to prevent the development of hepatocellular carcinoma.

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UNIVERSITÉ DE RENNES 1 CHU; Service des Maladies du Foie
rue Henri le Guilloux 2CS 46510
35033 RENNES
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