Archives of Toxicology

, Volume 92, Issue 9, pp 2829–2844 | Cite as

Effects of antiepileptic drugs on lipogenic gene regulation and hyperlipidemia risk in Taiwan: a nationwide population-based cohort study and supporting in vitro studies

  • Yi-Wen Li
  • Chung-Hsing Wang
  • Chao-Jung ChenEmail author
  • Charles C. N. Wang
  • Cheng-Li Lin
  • Wai-Kok Cheng
  • Hsin-Yi Shen
  • Yun-Ping LimEmail author
Molecular Toxicology


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.


Epilepsy Antiepileptic drugs Hyperlipidemia Valproate Liver X receptor alpha 



Acetyl-CoA carboxylase


ATP-citrate lyase


Antiepileptic drugs


Adjusted hazard ratio


Anatomical therapeutic chemical


Coronary artery disease




Confidence intervals




Chronic obstructive pulmonary disease


Cardiovascular disease


Defined daily dose




Direct repeat 4


Fatty acid


Fatty-acid elongase


Fatty-acid synthase




High-density lipoprotein cholesterol


Hazard ratio


International Classification of Diseases, Ninth Revision, Clinical Modification


Ischemic heart disease


Ligand-binding domain


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


Nuclear receptor




Protein Data Bank




Retinoid X receptor


Stearoyl-CoA desaturase-1


Sterol regulatory element binding protein-1c


Total cholesterol







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.

Author contributions

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.

Supplementary material

204_2018_2263_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1031 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yi-Wen Li
    • 1
  • Chung-Hsing Wang
    • 2
  • Chao-Jung Chen
    • 3
    • 4
    Email author
  • Charles C. N. Wang
    • 5
  • Cheng-Li Lin
    • 6
  • Wai-Kok Cheng
    • 1
  • Hsin-Yi Shen
    • 1
  • Yun-Ping Lim
    • 1
    • 7
    • 8
    Email author
  1. 1.Department of Pharmacy, College of PharmacyChina Medical UniversityTaichungTaiwan, Republic of China
  2. 2.Children’s Hospital of China Medical UniversityTaichungTaiwan, ROC
  3. 3.Graduate Institute of Integrated MedicineChina Medical UniversityTaichungTaiwan, ROC
  4. 4.Proteomics Core Laboratory, Department of Medical ResearchChina Medical University HospitalTaichungTaiwan, ROC
  5. 5.Department of Bioinformatics and Medical EngineeringAsia UniversityTaichungTaiwan, ROC
  6. 6.Management Office for Health DataChina Medical University HospitalTaichungTaiwan, ROC
  7. 7.Department of Internal MedicineChina Medical University HospitalTaichungTaiwan, ROC
  8. 8.Department of Medical ResearchChina Medical University HospitalTaichungTaiwan, ROC

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