Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors

Chanel A. Griggs, Scott W. Malm, Rosa Jaime-Frias, Catharine Smith

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop. In cells with an unsynchronized clock, VPA simultaneously upregulated the expression of genes encoding core circadian transcription factors that regulate the positive and negative limbs of the feedback loop. Using low dose glucocorticoid, we synchronized cultured fibroblast cells to a circadian oscillatory pattern. Whether VPA was added at the time of synchronization or 12 h later at CT12, we found that VPA disrupted the oscillatory expression of multiple genes encoding essential transcription factors that regulate circadian rhythm. Therefore, we conclude that VPA has a potent effect on the circadian rhythm transcription-translation feedback loop that may be linked to negative VPA side effects in humans. Furthermore, our study suggests potential chronopharmacology implications of VPA usage.

Original languageEnglish (US)
Pages (from-to)110-120
Number of pages11
JournalToxicology and Applied Pharmacology
Volume339
DOIs
StatePublished - Jan 15 2018

Fingerprint

Valproic Acid
Circadian Rhythm
Transcription Factors
Gene encoding
Transcription
Feedback
Clocks
Gene Expression
Circadian Clocks
Essential Genes
Hyperinsulinism
Fibroblasts
Hyperlipidemias
Migraine Disorders
Mood Disorders
Glucocorticoids
Weight Gain
Cultured Cells
Epilepsy
Synchronization

Keywords

  • Circadian rhythm
  • Glucocorticoids
  • Histone deacetylase inhibitor
  • Transcription

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors. / Griggs, Chanel A.; Malm, Scott W.; Jaime-Frias, Rosa; Smith, Catharine.

In: Toxicology and Applied Pharmacology, Vol. 339, 15.01.2018, p. 110-120.

Research output: Contribution to journalArticle

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