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Proliférateurs de peroxysomes et stress oxydant : impact de l'acide arachidonique et de l'acide clofibrique sur l'expression de protéines anti-oxydantes (métallothionéines et superoxydes dismutases) dans les cellules humaines HepG2

Abstract : Peroxysome proliferators and oxidizing stress: impact of arachidonic acid and clofibric acid on the expression of anti-oxidizing proteins (metallothioneins and superoxidize dismutases) in the human cells HepG2. Peroxysome Proliferator (PP) constitutes a family of chemical substances of different nature, which have in common the property to lead an increase of the number and of the enzymatic activities of the peroxysomes at the rodents. These activities produce reactive sorts of oxygen (ROS) who lead to a situation of oxidizing stress being able to infer hepatocarcinoma. Among these PP, this work was interested to clofibric acid, belonging to the family of fibrates used in the treatment of hyperlipidémia, and to arachidonic acid ( AA), a polyinsatured fatty acid, which plays a role of second messenger in different way, as in apoptose or in the cellular proliferation. The molecular mechanisms involved in these biologic response being badly known, this work presents the results obtained on human hepatoblastoma cells (HepG2) subjected to treatments with AA or clofibric acid. Marker of oxidant stress as well as expression of anti-oxidizing proteins were studied. Expression of an anti-oxidizing protein, metallothionein IIA, is strongly decreased by clofibric acid, independently of the nuclear receptor activated by the PP (PPAR). When HepG2 cell is treated with AA, expression of MnSOD, as well as its activity is induced for 24 hours of treatment with AA. However, an accumulation of H2O2 and products of lipid peroxidation is observed after 24 hours of treatment, this effects were abolished in the presence of inhibitors of AA metabolism. The study on the way of transduction of the signal leading to the induction of the MnSOD gene shows the importance of the p38 Mitogen Activated Protein Kinase (MAPK) pathway, activated by the ROS produced during the metabolism of AA, as well as proteins kinase C. Induction of the MnSOD gene by AA is correlated with AP-1 activation, herself dependent on the p38 MAPK.pathway. In conclusion, clofibric acid seems to have little effect on HepG2 cells, contrary to what is shown for the rodents. On the other hand, AA leads to an oxidative stress by the ROS produced by her metabolism, which play the role of second messenger by activating a way of transduction leading to an anti-oxidizing response, but accumulation of ROS induce oxidizing damages being able to modify the cellular life.
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http://docnum.univ-lorraine.fr/prive/SCD_T_2002_0024_BIANCHI.pdf
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https://hal.univ-lorraine.fr/tel-01746695
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Submitted on : Thursday, March 29, 2018 - 10:42:52 AM
Last modification on : Monday, October 19, 2020 - 12:09:00 PM

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  • HAL Id : tel-01746695, version 1

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Arnaud Bianchi. Proliférateurs de peroxysomes et stress oxydant : impact de l'acide arachidonique et de l'acide clofibrique sur l'expression de protéines anti-oxydantes (métallothionéines et superoxydes dismutases) dans les cellules humaines HepG2. Biologie moléculaire. Université Henri Poincaré - Nancy 1, 2002. Français. ⟨NNT : 2002NAN10024⟩. ⟨tel-01746695⟩

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