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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 Chen
  • Charles C. N. Wang
  • Cheng-Li Lin
  • Wai-Kok Cheng
  • Hsin-Yi Shen
  • Yun-Ping Lim
Molecular Toxicology
  • 74 Downloads

Abstract

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.

Keywords

Epilepsy Antiepileptic drugs Hyperlipidemia Valproate Liver X receptor alpha 

Abbreviations

ACC

Acetyl-CoA carboxylase

ACLY

ATP-citrate lyase

AEDs

Antiepileptic drugs

aHR

Adjusted hazard ratio

ATC

Anatomical therapeutic chemical

CAD

Coronary artery disease

CBZ

Carbamazepine

CIs

Confidence intervals

CLZ

Clonazepam

COPD

Chronic obstructive pulmonary disease

CVD

Cardiovascular disease

DDD

Defined daily dose

DMSO

Dimethylsulfoxide

DR4

Direct repeat 4

FA

Fatty acid

FAE

Fatty-acid elongase

FAS

Fatty-acid synthase

GBP

Gabapentin

HDL-C

High-density lipoprotein cholesterol

HR

Hazard ratio

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

IHD

Ischemic heart disease

LBD

Ligand-binding domain

LDL-C

Low-density lipoprotein cholesterol

LHID 2000

Longitudinal Health Insurance Database 2000

LXRα

Liver X receptor alpha

NAFLD

Non-alcoholic fatty liver disease

NHI

National Health Insurance

NHIRD

National Health Insurance Research Database

NR

Nuclear receptor

PB

Phenobarbital

PDB

Protein Data Bank

PHE

Phenytoin

RXR

Retinoid X receptor

SCD

Stearoyl-CoA desaturase-1

SREBP-1c

Sterol regulatory element binding protein-1c

TC

Total cholesterol

TGs

Triglycerides

VPA

Valproate

Notes

Acknowledgements

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
  • Charles C. N. Wang
    • 5
  • Cheng-Li Lin
    • 6
  • Wai-Kok Cheng
    • 1
  • Hsin-Yi Shen
    • 1
  • Yun-Ping Lim
    • 1
    • 7
    • 8
  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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