Back to Search
Start Over
Docosahexaenoic acid up-regulates both PI3K/AKT-dependent FABP7-PPARγ interaction and MKP3 that enhance GFAP in developing rat brain astrocytes.
- Source :
-
Journal of neurochemistry [J Neurochem] 2017 Jan; Vol. 140 (1), pp. 96-113. Date of Electronic Publication: 2016 Dec 07. - Publication Year :
- 2017
-
Abstract
- 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 (PPARγ)-dependent. We found that PI3K/AKT activated PPARγ that triggered FABP7 expression via PPARγ-responsive elements within its gene. Towards identifying FABP7-downstream pathways, we considered our previous report that demonstrated cyclin-dependent kinase-5 (CDK5)-PPARγ-protein-protein complex to suppress GFAP. We found that the DHA-induced FABP7 underwent protein-protein interaction with PPARγ, which impeded CDK5-PPARγ formation. Hence, it appeared that enhanced FABP7-PPARγ in lieu of CDK5-PPARγ resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7-PPARγ protein-protein complex, but also up-regulated a FABP7-independent MAP-kinase-phosphatase-3 pathway that inactivated CDK5 and hence attenuated CDK5-PPARγ. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7-PPARγ, through genomic and non-genomic mechanisms, and MAP-kinase-phosphatase-3 that converged at attenuated CDK5-PPARγ and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA-mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development.<br /> (© 2016 International Society for Neurochemistry.)
- Subjects :
- Animals
Astrocytes drug effects
Brain drug effects
Brain growth & development
Brain metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Female
Male
Protein Binding physiology
Rats
Rats, Wistar
Up-Regulation drug effects
Up-Regulation physiology
Astrocytes metabolism
Docosahexaenoic Acids pharmacology
Dual Specificity Phosphatase 6 biosynthesis
Fatty Acid-Binding Protein 7 biosynthesis
Glial Fibrillary Acidic Protein biosynthesis
Oncogene Protein v-akt biosynthesis
PPAR gamma biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 140
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27787894
- Full Text :
- https://doi.org/10.1111/jnc.13879