title: 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 ofRSB1, which encodes an exporter of long chain bases dihydrosphingosine (DHS) and phytosphingosine (PHS), and further saw that VPA increased sensitivity of anrsb1Δ 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, inrsb1Δ cells. Expression ofORMgenes (negative regulators of PHS synthesis) and of fatty acid elongase genesFEN1andSUR4were decreased, and expression ofYOR1(exporter of PHS-1P) andDPL1(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 anino1Δ 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.
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202.
authors.forename: Shyamalagauri
authors.initials: S
authors.lastname: Jadhav
authors.affiliation: the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and.|the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425.
authors.forename: Sarah
authors.initials: S
authors.lastname: Russo
authors.affiliation: the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and.|the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425.
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Cowart
authors.affiliation: From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202, mgreenberg@wayne.edu.
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Greenberg
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy; D002518:Ceramides / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D002518:Ceramides; D008565:Membrane Proteins; C465340:RSB1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D007294:Inositol; D014635:Valproic Acid; D000123:Acetyltransferases; C107118:ELO2 protein, S cerevisiae; C107119:SUR4 protein, S cerevisiae; C012491:phytosphingosine; D013110:Sphingosine
keywords: ceramide; inositol; lipid metabolism; sphingolipid; valproate; yeast; yeast metabolism