A PPARs cross‐talk concertedly commits C6 glioma cells to oligodendrocytes and induces enzymes involved in myelin synthesis

Abstract

Peroxisome proliferator activated receptors (PPARs, alpha, beta/delta, gamma) control lipid homeostasis and differentiation in various tissues and tumor cells. PPARbeta and PPARgamma increase oligodendrocyte maturation in glial mixed populations and spinal cord oligodendrocytes, respectively, and PPARbeta 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 PPARgamma shows transcriptional activity in agonist-based reporter gene assay. Agonist-activated PPARgamma 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 PPARgamma overexpressing cells, which in addition show PPARbeta up-regulation. PPARbeta or PPARalpha agonists show no effect. Nevertheless, PPARbeta overexpression up-regulates PPARgamma and commits C6 cells to oligodendrocytes; effect that is abrogated by a PPARgamma antagonist or PPARgamma interference RNA. Moreover, PPARbeta overexpression also induces PPARalpha 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 PPARbeta might be essential for increasing oligodendrocyte distinctive markers and enzymes required for myelin synthesis in C6 glioma cells through up-regulation of PPARgamma and PPARalpha.

Peroxisome Proliferator-Activated Receptor (PPAR)-γ Positively Controls and PPARα Negatively Controls Cyclooxygenase-2 Expression in Rat Brain Astrocytes through a Convergence on PPARβ/δ via Mutual Control of PPAR Expression Levels

“…We further found that activation of PPAR␥ did not influence the PPAR␣ expression. This finding is consistent with findings by others in C6 glioma cells (Leisewitz et al, 2008). The positive-negative loop, as found in the present investigation, can control target gene expression via a complex tuning mechanism, as suggested by the full scheme in Fig.…”

“…PPAR␤/␦ activation by agonists or PPAR␤/␦ overexpression inhibits PPAR␥ (Shi et al, 2002;Zuo et al, 2006) and PPAR␣ activity (Shi et al, 2002) in both cancer and normal cells. It was also shown that the synthetic PPAR␤/␦ agonists increase PPAR␥-induced differentiation of adipocytes (Matsusue et al, 2004) or C6 glioma cells (Leisewitz et al, 2008). Thus, the interplay between PPAR isoforms and the type of PPAR, which might play the role of the central switch, depend on the cellular context or the target gene.…”

Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state

“…For example, its activation promotes cholesterol efflux from macrophages and enhances reverse cholesterol transport (RCT) by strongly inducing expression of genes that encode the cholesterol transporter ABCA1 ( 35 ). Moreover, PPAR ␣ activation facilitates the biosynthesis of Pls ( 36 ) as well as apolipoprotein A-I, as seen by the resultant increased plasma HDL and Pls levels.…”

PPAR Agonists as Therapeutics for CNS Trauma and Neurological Diseases

“…Furthermore, PPARγ activation directly promotes differentiation of rat OPCs into mature oligodendrocytes (Bernardo et al, 2009). Since myelin is composed mostly of lipid and since PPARs play a major role in lipid metabolism, it is not surprising that PPARs regulate the differentiation and function of oligodendrocytes (Saluja et al, 2001; Leisewitz et al, 2008; Kanakasabai et al, 2012). Statins (cholesterol-reducing drugs) also promote oligodendrocyte maturation by inducing PPARγ, an effect that is blocked by PPARγ antagonism (Sim et al, 2008).…”