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Valproate increases ceramide levels and induces the unfolded protein response
Author(s) -
Jadhav Shyamalagauri,
Russo Sarah,
Cowart Ashley,
Greenberg Miriam
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1136.1
Subject(s) - ceramide , unfolded protein response , chemistry , downregulation and upregulation , sphingolipid , biochemistry , valproic acid , amino acid , microbiology and biotechnology , biology , gene , apoptosis , epilepsy , neuroscience
Bipolar disorder (BD), which is characterized by depression and mania, affects about 1% of the world population. Current treatments are effective in only 40–60% of cases and cause severe side effects. Valproic acid (VPA), a branched short‐chain fatty acid, is one of the most widely used drugs for the treatment BD. Although many hypotheses have been postulated to explain the molecular mechanism of action of this drug in BD, the therapeutic mechanism is not understood. This knowledge gap has hampered the development of new drugs to treat this disorder. To identify candidate pathways affected by VPA, we performed a genome wide expression analysis in yeast cells grown in the presence and absence of VPA. In response to VPA, we observed upregulation of FEN1 and SUR4 , encoding fatty acid elongases that catalyze the synthesis of very long chain fatty acids (C24 to C26) required for the synthesis of ceramide. Interestingly, fen1Δ and sur4Δ exhibit VPA sensitivity. VPA also increases levels of ceramides, especially those that contain C24 and C26 fatty acids. Ceramide acts as a signaling molecule that downregulates the expression of amino acid transporters and induces stress by reducing the intracellular levels of amino acids. Consistent with an increase in ceramide, VPA decreases the expression of amino acid transporters. In addition, VPA increases the expression of ER chaperone proteins (markers of UPR) as well as activates the unfolded protein response element (UPRE), suggesting that VPA induces the UPR pathway. In the presence of the ceramide synthase inhibitor fumonisin, the UPR pathway is not induced by VPA, suggesting that VPA induction of the UPR is mediated by ceramide. Studies show that BD patients exhibit a decreased UPR activation, decreased expression of ER chaperone proteins and a (‐116C‐‐>G) polymorphism in XBP1, a key transcription factor that upregulates the UPR. This study identifies the UPR pathway as a potential new target that could be important in the therapeutic action of VPA.