Biological activities of the LXRalpha and beta agonist, 4beta-hydroxycholesterol, and of its isomer, 4alpha-hydroxycholesterol, on oligodendrocytes: effects on cell growth and viability, oxidative and inflammatory status.
Fiche publication
Date publication
mars 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LIZARD Gérard
Tous les auteurs :
Nury T, Samadi M, Varin A, Lopez T, Zarrouk A, Boumhras M, Riedinger JM, Masson D, Vejux A, Lizard G
Lien Pubmed
Résumé
The biochemical and biological properties of 4beta-hydroxycholesterol and of its isomer, 4alpha-hydroxycholesterol, are not well known. So, we determined the ability of 4alpha- and 4beta-hydroxycholesterol to react with LXRalpha and LXRbeta, and we characterized the activities of these oxysterols on oligodendrocytes which are myelin synthesizing cells. The effects of 4alpha- and 4beta-hydroxycholesterol were studied on 158N murine oligodendrocytes to assess their activities on cell growth and viability, oxidative and inflammatory status. To this end different parameters were used: cell counting with trypan blue; identification of dead cells and cell cycle analysis with propidium iodide; evaluation of mitochondrial depolarization, lysosomal membrane integrity, actin depolimerization, nuclear morphology, and superoxide anion production after staining with JC-1, acridine orange, rhodamine-phalloidin, Hoechst 33342, and dihydroethidium, respectively; evaluation of ultrastructural changes by transmission electron microscopy, and cytokine quantification with a cytometric bead array. Only 4beta-hydroxycholesterol is a LXRalpha and beta agonist. No cytotoxic effects were found with 4alpha-hydroxycholesterol except a slight inhibition of cell growth at elevated concentrations. At high concentrations, 4beta-hydroxycholesterol was not only able to inhibit cell growth, but also to induce cell death associated with a loss of mitochondrial transmembrane potential, dysfunctions of lysosomal membrane integrity, and superoxide anion overproduction. These side effects were lower than those observed with 7-ketocholesterol and 25-hydroxycholesterol used as positive controls. On oligodendrocyte murine primary cultures, only lysosomal membrane integrity was slightly affected under treatment with 4alpha- and 4beta-hydroxycholesterol. So, 4alpha- and 4beta-hydroxycholesterol have different biological activities. Their ability to induce cytotoxic effects on oligodendrocytes can be considered as weak comparatively to 7-ketocholesterol and 25-hydroxycholesterol.
Référence
Biochimie. 2013 Mar;95(3):518-30