ArticleThe Journal of biological chemistry2016
Valproate Induces the Unfolded Protein Response by Increasing Ceramide Levels.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Inositol biosynthesis is inversely regulated by glycolytic activity.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Article
- Fungal Sphingolipids: Biosynthesis Pathways, Structural Features and Biological Functions.Journal of fungi (Basel, Switzerland) · 2026Review
- Sphingolipids in Emotional Well-Being.Journal of neurochemistry · 2026Review
- Valproate independently activates Snf1, inhibits TORC1, and induces repression of INO1 transcription by increasing nuclear localization of Opi1.Scientific reports · 2025Article
- New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.Pharmacological reviews · 2024Review
- Untargeted Lipidomics Study of Bipolar Disorder Patients in Serbia.International journal of molecular sciences · 2023Article
- Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury.Molecules (Basel, Switzerland) · 2023Review
- Alterations of Plasma Lipids in Adult Women With Major Depressive Disorder and Bipolar Depression.Frontiers in psychiatry · 2022Article
- Alterations in the Plasma Lipidome of Adult Women With Bipolar Disorder: A Mass Spectrometry-Based Lipidomics Research.Frontiers in psychiatry · 2022Article
- The Role of the UPR Pathway in the Pathophysiology and Treatment of Bipolar Disorder.Frontiers in cellular neuroscience · 2021Review
- Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae.Scientific reports · 2020Article
- Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods.Advanced drug delivery reviews · 2020Review
- Lipidomic Profiling Reveals Disruption of Lipid Metabolism in Valproic Acid-Induced Hepatotoxicity.Frontiers in pharmacology · 2019Article
- pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 ménage-à-trois to stress tolerance and longevity.Microbial cell (Graz, Austria) · 2018Review
- Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder.Neurochemical research · 2018Review
- Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine.The Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.