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J. Biol. Chem., Vol. 278, Issue 34, 31504-31511, August 22, 2003

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Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia^*

Karine Robert , Jean-François Chassé , Dominique Santiard-Baron ¶, Catherine Vayssettes ||, Allel Chabli ||, Joelle Aupetit ||, Nobuyo Maeda **, Pierre Kamoun ||, Jacqueline London and Nathalie Janel 

From the EA 3508, Université Paris 7, Denis Diderot, Case 7104, 2 Place Jussieu, 75251 Paris Cedex, France, INSERM U490, Faculté de Médecine Necker, 75743 Paris Cedex 15, France, ^¶Central Nervous System Department, Aventis, 94403 Vitry sur Seine, France, ^||Laboratoire de Biochimie Médecine B, Hopital Necker-Enfants Malades, France, and ^**Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599

Cystathionine -synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.

Received for publication, December 20, 2002 , and in revised form, June 2, 2003.

^* This work was supported in part by the Fondation Jérome Lejeune and European Union Grant QLRT-2001-00816. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Fellowship of the Fondation Jérome Lejeune.

To whom correspondence should be addressed. Tel.: 33-1-44-27-77-45; Fax: 33-1-44-27-83-38; E-mail: janel{at}paris7.jussieu.fr.

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