Browsing by Author "Loyola, Gloria"

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    A PPARs cross-talk concertedly commits C6 glioma cells to oligodendrocytes and induces enzymes involved in myelin synthesis
    (WILEY, 2008) Leisewitz, Andrea V.; Urrutia, Carolina R.; Martinez, Gabriela R.; Loyola, Gloria; Bronfman, Miguel
    Peroxisome proliferator activated receptors (PPARs, alpha, beta/delta, gamma) control lipid homeostasis and differentiation in various tissues and tumor cells. PPAR beta and PPAR gamma increase oligodendrocyte maturation in glial mixed populations and spinal cord oligodendrocytes, respectively, and PPAR beta 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 PPAR gamma shows transcriptional activity in agonist-based reporter gene assay. Agonist-activated PPAR gamma 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 PPAR gamma overexpressing cells, which in addition show PPAR beta up-regulation. PPAR beta or PPAR alpha agonists show no effect. Nevertheless, PPAR beta overexpression up-regulates PPAR gamma and commits C6 cells to oligodendrocytes: effect that is abrogated by a PPAR gamma antagonist or PPAR gamma interference RNA. Moreover, PPAR beta overexpression also induces PPAR alpha 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 PPAR beta might be essential for increasing oligodendrocyte distinctive markers and enzymes required for myelin synthesis in C6 glioma cells through up-regulation of PPAR gamma and PPAR alpha.
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    Characterization of an Agarophyton chilense Oleoresin Containing PPARγ Natural Ligands with Insulin-Sensitizing Effects in a C57Bl/6J Mouse Model of Diet-Induced Obesity and Antioxidant Activity in Caenorhabditis elegans
    (2021) Pinto, Claudio; Raquel Ibanez, Maria; Loyola, Gloria; Leon, Luisa; Salvatore, Yasmin; Gonzalez, Carla; Barraza, Victor; Castaneda, Francisco; Aldunate, Rebeca; Contreras-Porcia, Loretto; Fuenzalida, Karen; Bronfman, Francisca C.
    The biomedical potential of the edible red seaweed Agarophyton chilense (formerly Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPAR gamma nuclear receptor. PPAR gamma is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. Medical use of TZDs is limited due to undesired side effects, a problem that has triggered the search for selective PPAR gamma modulators (SPPARMs) without the TZD side effects. We produced Agarophyton chilense oleoresin (Gracilex(R)), which induces PPAR gamma activation without inducing adipocyte differentiation, similar to SPPARMs. In a diet-induced obesity model of male mice, we showed that treatment with Gracilex(R) improves insulin sensitivity by normalizing altered glucose and insulin parameters. Gracilex(R) is enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as tocopherols and beta-carotene. Accordingly, Gracilex(R) possesses antioxidant activity in vitro and increased antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex(R) represents a good source of natural PPAR gamma ligands and antioxidants with the potential to mitigate metabolic disorders. Thus, its nutraceutical value in humans warrants further investigation.
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    P450CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPAR alpha-dependent peroxisomal proliferation
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007) Gatica, Arnaldo; Aguilera, Mauricio C.; Contador, David; Loyola, Gloria; Pinto, Claudio O.; Amigo, Ludwig; Tichauer, Juan E.; Zanlungo, Silvana; Bronfman, Miguel
    Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferator-activated receptor (PPAR) alpha subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. omega-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A omega-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPAR alpha in vitro and as PPAR alpha activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A omega-hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPAR alpha ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPAR alpha downstream targets.