Effects of antiepileptic drugs on lipogenic gene regulation and hyperlipidemia risk in Taiwan: a nationwide population-based cohort study and supporting in vitro studies
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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 (LXRα) 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 LXRα. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRα 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.
KeywordsEpilepsy Antiepileptic drugs Hyperlipidemia Valproate Liver X receptor alpha
Adjusted hazard ratio
Anatomical therapeutic chemical
Coronary artery disease
Chronic obstructive pulmonary disease
Defined daily dose
Direct repeat 4
High-density lipoprotein cholesterol
International Classification of Diseases, Ninth Revision, Clinical Modification
Ischemic heart disease
Low-density lipoprotein cholesterol
- LHID 2000
Longitudinal Health Insurance Database 2000
Liver X receptor alpha
Non-alcoholic fatty liver disease
National Health Insurance
National Health Insurance Research Database
Protein Data Bank
Retinoid X receptor
Sterol regulatory element binding protein-1c
This study was supported by the Ministry of Science and Technology, Taiwan, R.O.C. (MOST107-2320-B-039-042-MY3), China Medical University, Taichung, Taiwan (CMU106-ASIA-22), partially supported by the 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, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. We thank Professor David J. Mangelsdorf (Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA) and Professor Marta Casado (Instituto de Biomedicina de Valencia, IBV-CSIC, Jaime Roig 11, 46010 Valencia, Spain) for providing the LXRα and the reporter constructs.
Conceived of or designed study: YL, CW, CC, and YL; performed research: all authors; analyzed data: all authors; contributed new methods or models: CCNW; wrote the paper: all authors.
Compliance with ethical standards
Conflict of interest
The authors have declared that no competing interests exist.
Informed consent and ethical approval
The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received, and prescriptions. Therefore, patient consent is not required to access the NHIRD. This study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH106-REC1-136). The IRB also specifically waived the consent requirement.
- Barbara BG, DiPiro JT, Schwinghammer TL (2012) Pharmacotherapy handbook, 9th edn. The McGraw-Hill Companies, Inc, New YorkGoogle Scholar
- Grefhorst A, Elzinga BM, Voshol PJ, Plösch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F (2002) Stimulation of lipogenesis by pharmacological activation of the liver x receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277:34182–34190CrossRefPubMedGoogle Scholar
- Krumholz A, Shinnar S, French J, Gronseth G, Wiebe S (2015) Evidence-based guideline: Management of an unprovoked first seizure in adults: report of the guideline development subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 85:1526–1527CrossRefPubMedGoogle Scholar
- Leonardi M, Ustun TB (2002) The global burden of epilepsy. Epilepsia 43(Suppl 6):21–25Google Scholar
- Luef G, Rauchenzauner M, Waldmann M, Sturm W, Sandhofer A, Seppi K, Trinka E, Unterberger I, Ebenbichler CF, Joannidis M, Walser G, Bauer G, Hoppichler F, Lechleitner M (2009) Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res 86:42–47CrossRefPubMedGoogle Scholar
- National Health Insurance Research Database, Taiwan. http://nhird.nhri.org.tw/en/index.htm (cited in 2016)
- Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14:2819–2830CrossRefPubMedPubMedCentralGoogle Scholar