Abstract
Bipolar disorder (BD), which is characterized by depression and mania, affects 1-2% of the world population. Current treatments are effective in only 40-60% of cases and cause severe side effects. Valproate (VPA) is one of the most widely used drugs for the treatment of BD, but the therapeutic mechanism of action of this drug is not understood. This knowledge gap has hampered the development of effective treatments. To identify candidate pathways affected by VPA, we performed a genome-wide expression analysis in yeast cells grown in the presence or absence of the drug. VPA caused up-regulation of FEN1 and SUR4, encoding fatty acid elongases that catalyze the synthesis of very long chain fatty acids (C24 to C26) required for ceramide synthesis. Interestingly, fen1Δ and sur4Δ mutants exhibited VPA sensitivity. In agreement with increased fatty acid elongase gene expression, VPA increased levels of phytoceramide, especially those containing C24-C26 fatty acids. Consistent with an increase in ceramide, VPA decreased the expression of amino acid transporters, increased the expression of ER chaperones, and activated the unfolded protein response element (UPRE), suggesting that VPA induces the UPR pathway. These effects were rescued by supplementation of inositol and similarly observed in inositol-starved ino1Δ cells. Starvation of ino1Δ cells increased expression of FEN1 and SUR4, increased ceramide levels, decreased expression of nutrient transporters, and induced the UPR. These findings suggest that VPA-mediated inositol depletion induces the UPR by increasing the de novo synthesis of ceramide.
Highlights
Bipolar disorder (BD), which is characterized by depression and mania, affects 1–2% of the world population
We show that VPA induces the unfolded protein response (UPR) by increasing ceramide levels via inositol depletion
Our specific findings indicated that VPA 1) increased expression of fatty acid elongases synthesizing C24 and C26 fatty acids; 2) increased ceramide levels, PHC with C24 –C26 fatty acids; 3) decreased the expression of amino acid transporters; and 4) induced the UPR pathway
Summary
Interdependence of the UPR pathway and ceramide synthesis has been demonstrated in yeast and mammals. Induction of the UPR increases ceramide levels and viability in yeast [30]. Perturbation of de novo synthesis of sphingolipids activates the UPR in yeast [29, 31], and defective ceramide homeostasis leads to UPR failure [32]. We show for the first time that VPAmediated inositol depletion induces the UPR pathway by increasing de novo synthesis of ceramide, especially C24 –C26containing phytoceramide. These findings have implications for the therapeutic mechanism of VPA
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