Docosahexaenoic acid up-regulates both PI3K/AKT-dependent FABP7PPAR gamma interaction and MKP3 that enhance GFAP in developing rat brain astrocytes

摘要

The astrocyte marker, glial fibrillary acidic protein (GFAP), has essential functions in the brain, but may trigger astroglial scarring when expressed in excess. Docosahexaenoic acid (DHA) is an n-3 fatty acid that is protective during brain development. However, the effect of DHA on GFAP levels of developing brain remains unexplored. Here, we detected that treating developing rats with DHA-enriched fish-oil caused dose-dependent GFAP augmentation. We investigated the mechanism promoting GFAP, hypothesizing the participation of fatty acid-binding protein-7 (FABP7), known to bind DHA. We identified that DHA stimulated FABP7 expression in astrocytes, and FABP7-silencing suppressed DHA-induced GFAP, indicating FABP7-mediated GFAP increase. Further investigation proved FABP7 expression to be phosphatidylinositide 3-kinases (PI3K)/AKT and nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma)dependent. We found that PI3K/AKT activated PPAR gamma that triggered FABP7 expression via PPAR gamma-responsive elements within its gene. Towards identifying FABP7-downstream pathways, we considered our previous report that demonstrated cyclin-dependent kinase- 5 (CDK5)-PPAR gamma-protein-protein complex to suppress GFAP. We found that the DHA-induced FABP7underwentprotein-protein interaction with PPAR gamma, which impeded CDK5-PPAR gamma formation. Hence, it appeared that enhanced FABP7-PPAR gamma in lieu of CDK5-PPAR gamma resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7-PPAR gamma protein-protein complex, but also up-regulated a FABP7-independent MAP-kinase-phosphatase-3 pathway that inactivated CDK5 and hence attenuated CDK5-PPAR gamma. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7-PPAR gamma, through genomic and non-genomic mechanisms, and MAP-kinase-phosphatase-3 that converged at attenuated CDK5-PPAR gamma and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA-mediated astroglial hyperactivation, pointing toward aprobable injurious role of DHA in brain development.