Abstract

Peroxisome proliferator activated receptors (PPARs, α, β/δ, γ) control lipid homeostasis and differentiation in various tissues and tumor cells. PPARβ and PPARγ increase oligodendrocyte maturation in glial mixed populations and spinal cord oligodendrocytes, respectively, and PPARβ is known to modulate the activity of other PPARs. To assess a possible interaction between PPARs in glial cell differentiation we used the undifferentiated C6 glioma cell line as model. These cells express all three PPARs, but only PPARγ shows transcriptional activity in agonist-based reporter gene assay. Agonist-activated PPARγ up-regulates oligodendrocyte markers, down-regulates an astrocyte marker, and increases alkyl-dihydroxyacetone phosphate synthase, enzyme involved in the synthesis of myelin-rich plasmalogens. Similar effects are induced in PPARγ overexpressing cells, which in addition show PPARβ up-regulation. PPARβ or PPARα agonists show no effect. Nevertheless, PPARβ overexpression up-regulates PPARγ and commits C6 cells to oligodendrocytes; effect that is abrogated by a PPARγ antagonist or PPARγ interference RNA. Moreover, PPARβ overexpression also induces PPARα and its target genes, including acyl-CoA oxidase, enzyme involved in very long chain fatty acid recycling, and in the synthesis of myelin components such as docosahexaenoic acid. These results indicate for the first time, that PPARs concertedly cooperate in C6 glioma cell differentiation to oligodendrocytes. Further, they suggest that active PPARβ might be essential for increasing oligodendrocyte distinctive markers and enzymes required for myelin synthesis in C6 glioma cells through up-regulation of PPARγ and PPARα. © 2008 Wiley-Liss, Inc.