Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors
| Autor: | Scott W. Malm, Chanel A. Griggs, Catharine L. Smith, Rosa Jaime-Frias |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Transcriptional Activation
0301 basic medicine medicine.medical_specialty medicine.drug_class Circadian clock Gene Expression Biology Toxicology Article Mice 03 medical and health sciences Downregulation and upregulation Cell Line Tumor Internal medicine Gene expression medicine Animals Circadian rhythm Transcription factor Pharmacology Valproic Acid Dose-Response Relationship Drug Histone deacetylase inhibitor Circadian Rhythm 030104 developmental biology Endocrinology NIH 3T3 Cells Anticonvulsants lipids (amino acids peptides and proteins) Glucocorticoid Transcription Factors medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 339:110-120 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2017.12.005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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