title: Docosahexaenoic acid up-regulates both PI3K/AKT-dependent FABP7-PPARγ interaction and MKP3 that enhance GFAP in developing rat brain astrocytes.
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.
authors: Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Lucknow, India.|Amity Institute of Biotechnology, Amity University (Lucknow campus), Lucknow, India.
authors: Sachin
authors: S
authors: Tripathi
authors: Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR campus, Lucknow, India.
authors: Rajesh
authors: R
authors: Kushwaha
authors: Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Lucknow, India.|Babu Banarasi Das University, Lucknow, India.
authors: Juhi
authors: J
authors: Mishra
authors: Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR campus, Lucknow, India.|Analytical Chemistry Laboratory and Regulatory Toxicology group, CSIR-IITR, Lucknow, India.
authors: Manoj Kumar
authors: MK
authors: Gupta
authors: Division of Biochemistry, CSIR-Central Drug Research Institute (CDRI), Lucknow, India.
authors: Harish
authors: H
authors: Kumar
authors: Amity Institute of Biotechnology, Amity University (Lucknow campus), Lucknow, India.
authors: Somali
authors: S
authors: Sanyal
authors: Central Pathology Laboratory, CSIR-IITR, Lucknow, India.
authors: Dhirendra
authors: D
authors: Singh
authors: Division of Biochemistry, CSIR-Central Drug Research Institute (CDRI), Lucknow, India.
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Division of Molecular and Structural Biology, CSIR-CDRI, Lucknow, India.
authors: Amogh Anant
authors: AA
authors: Sahasrabuddhe
authors: Environmental Biotechnology Laboratory, Environmental Toxicology Group, CSIR-IITR, Lucknow, India.
authors: Mohan
authors: M
authors: Kamthan
authors: Mass& Analytical (NCMS) Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.
authors: Mohana Krishna Reddy
authors: MK
authors: Mudiam
authors: Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR campus, Lucknow, India.
authors: Sanghamitra
authors: 0000-0002-1490-3599
authors: S
authors: Bandyopadhyay
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054642:Dual Specificity Phosphatase 6 / Q000096:biosynthesis*; D000071438:Fatty Acid-Binding Protein 7 / Q000096:biosynthesis*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis*; D008297:Male; D051058:Oncogene Protein v-akt / Q000096:biosynthesis*; D047495:PPAR gamma / Q000096:biosynthesis*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D047495:PPAR gamma; D004281:Docosahexaenoic Acids; D051058:Oncogene Protein v-akt; D054642:Dual Specificity Phosphatase 6
keywords: 
  AKT
  ; ERK-inactivation; FABP7; astrocyte activation; n-3 fatty acid