Journal
ARCHIVES OF TOXICOLOGY
Volume 92, Issue 9, Pages 2829-2844Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-018-2263-3
Keywords
Epilepsy; Antiepileptic drugs; Hyperlipidemia; Valproate; Liver X receptor alpha
Categories
Funding
- Ministry of Science and Technology, Taiwan, R.O.C. [MOST107-2320-B-039-042-MY3]
- China Medical University, Taichung, Taiwan [CMU106-ASIA-22]
- Taiwan Ministry of Health and Welfare, Taiwan [MOHW107-TDU-B-212-123004]
- China Medical University Hospital
- Academia Sinica Stroke Biosignature Project [BM10701010021]
- MOST Clinical Trial Consortium for Stroke [MOST106-2321-B-039-005]
- Tseng-Lien Lin Foundation, Taichung, Taiwan
- Katsuzo and Kiyo Aoshima Memorial Funds, Japan
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To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXR alpha) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand-binding domain of LXR alpha. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXR alpha activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended.
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