Premium
Docosahexaenoic acid up‐regulates both PI 3K/ AKT ‐dependent FABP 7– PPAR γ interaction and MKP 3 that enhance GFAP in developing rat brain astrocytes
Author(s) -
Tripathi Sachin,
Kushwaha Rajesh,
Mishra Juhi,
Gupta Manoj Kumar,
Kumar Harish,
Sanyal Somali,
Singh Dhirendra,
Sanyal Sabyasachi,
Sahasrabuddhe Amogh Anant,
Kamthan Mohan,
Mudiam Mohana Krishna Reddy,
Bandyopadhyay Sanghamitra
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13879
Subject(s) - protein kinase b , docosahexaenoic acid , pi3k/akt/mtor pathway , glial fibrillary acidic protein , fatty acid binding protein , biology , cyclin dependent kinase 5 , protein kinase a , chemistry , biochemistry , kinase , microbiology and biotechnology , signal transduction , fatty acid , polyunsaturated fatty acid , immunology , mitogen activated protein kinase kinase , immunohistochemistry , gene
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 ( FABP 7), known to bind DHA . We identified that DHA stimulated FABP 7 expression in astrocytes, and FABP 7‐silencing suppressed DHA ‐induced GFAP , indicating FABP 7‐mediated GFAP increase. Further investigation proved FABP 7 expression to be phosphatidylinositide 3‐kinases ( PI 3K)/ AKT and nuclear receptor peroxisome proliferator‐activated receptor‐gamma ( PPAR γ)‐dependent. We found that PI 3K/ AKT activated PPAR γ that triggered FABP 7 expression via PPAR γ‐responsive elements within its gene. Towards identifying FABP 7‐downstream pathways, we considered our previous report that demonstrated cyclin‐dependent kinase‐5 ( CDK 5)‐ PPAR γ‐protein–protein complex to suppress GFAP . We found that the DHA ‐induced FABP 7 underwent protein‐protein interaction with PPAR γ, which impeded CDK 5‐ PPAR γ formation. Hence, it appeared that enhanced FABP7‐ PPAR γ in lieu of CDK 5‐ PPAR γ resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP 7‐ PPAR γ protein‐protein complex, but also up‐regulated a FABP 7‐independent MAP ‐kinase‐phosphatase‐3 pathway that inactivated CDK 5 and hence attenuated CDK 5‐ PPAR γ. Overall, our data reveal that via the proximal PI 3K/ AKT , DHA induces FABP 7‐ PPAR γ, through genomic and non‐genomic mechanisms, and MAP ‐kinase‐phosphatase‐3 that converged at attenuated CDK 5‐ PPAR γ and therefore, enhanced GFAP . Accordingly, our study demonstrates a DHA ‐mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development.