Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine

Abstract

Bipolar disorder (BD) is a severe psychiatric illness affecting ∼1% of the world population. Valproate (VPA) and lithium, widely used for the treatment of BD, are not universally effective. These drugs have been shown to cause inositol depletion, but translating this observation to a specific therapeutic mechanism has been difficult, hampering the development of more effective therapies. We have shown previously in yeast that chronic VPA treatment induces the unfolded protein response due to increasing ceramide levels. To gain insight into the mechanisms activated during acute VPA treatment, we performed a genome-wide expression study in yeast treated with VPA for 30 min. We observed increased mRNA and protein levels of , which encodes an exporter of long chain bases dihydrosphingosine (DHS) and phytosphingosine (PHS), and further saw that VPA increased sensitivity of anΔ mutant to PHS, suggesting that VPA increases long chain base levels. Consistent with this, PHS levels were elevated in wild type and, to a greater extent, in Δ cells. Expression of genes (negative regulators of PHS synthesis) and of fatty acid elongase genes and were decreased, and expression of (exporter of PHS-1P) and (lyase that degrades DHS-1P and PHS-1P) was increased. These effects were more pronounced in medium lacking inositol, and were mirrored by inositol starvation of an Δ mutant. These findings provide a metabolic explanation as to how VPA-mediated inositol depletion causes increased synthesis of PHS and further support the therapeutic relevance of inositol depletion as a bipolar disorder treatment.

Mammalian sphingoid bases: Biophysical, physiological and pathological properties

“…Recently, Jadhav and collaborators have shown that treatment of yeast cells with valproate (VPA), a widely used drugs to treat bipolar disorder (BD), increases the levels of PhytoSO via de novo synthesis and at the same time leading to inositol depletion and upregulation of unfolded protein response [206]. They further demonstrated that VPA mediated increase in SL de novo synthesis is due to a downregulation of Orm1/2 expression, and upregulation of expression of fatty acid elongases Sur4 and Fen1, as well as of genes involved in the export and metabolism of PhytoSO [206,207]. Since, VPA induced inositol depletion is also observed in mammalian cell models [208,209] these findings suggest that inositol depletion and the consequent increase in PhytoSO levels might underlie the therapeutic action of VPA [207], which is promising for the development of new therapeutic approaches for BD treatment.…”

WITHDRAWN: Mammalian sphingoid bases: Biophysical, physiological and pathological properties

“…They further demonstrated that VPA mediated increase in SL de novo synthesis is due to a downregulation of Orm1/2 expression, and upregulation of expression of fatty acid elongases Sur4 and Fen1, as well as of genes involved in the export and metabolism of PhytoSO [206,207]. Since, VPA induced inositol depletion is also observed in mammalian cell models [208,209] these findings suggest that inositol depletion and the consequent increase in PhytoSO levels might underlie the therapeutic action of VPA [207], which is promising for the development of new therapeutic approaches for BD treatment.…”

Valproate activates the Snf1 kinase in Saccharomyces cerevisiae by decreasing the cytosolic pH

“…J o u r n a l P r e -p r o o f inhibition-A previously reported microarray analysis of the yeast gene expression response to VPA suggested altered expression of metabolic genes (28). qPCR analysis indicated no change in SUC2 (invertase; sucrose metabolism) expression and increased expression of POX1 (fatty-acyl CoA oxidase; β-oxidation), CIT2 and MLS1 (citrate synthase 2 and malate synthase; glyoxylate cycle), PCK1 (phosphoenolpyruvate carboxykinase; gluconeogenesis), and CAT2 (carnitine acetyl-CoA transferase; carnitine shuttle) in response to VPA treatment (1 mM, 30 min) (Fig.…”

“…Cross-species functionality has been demonstrated from yeast to mammalian cells, and the yeast model has been pivotal in identifying mammalian upstream activating kinases (27). Interestingly, a microarray analysis J o u r n a l P r e -p r o o f conducted to identify pathways affected by VPA in yeast revealed a pattern of altered expression of metabolic genes that is similar to the pattern observed during Snf1 activation (28,29). In the current study, we further exploited the yeast model to gain insight into the mechanism of activation of SNF1/AMPK by VPA.…”

“…In addition to carbon stress, Snf1 is activated in response to other environmental stressors, even in the presence of glucose (34). Interestingly, the microarray study cited above was conducted in conditions of high glucose when Snf1 is not usually activated (28), suggesting that VPA treatment substantially impacts energy metabolism. One of the main downstream targets of Snf1 is the transcriptional repressor Mig1 (35).…”