Skip to main content

Advertisement

SpringerLink
Log in

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

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

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

References

  • Aravindhan K, Webb CL, Jaye M, Ghosh A, Willette RN, DiNardo NJ, Jucker BM (2006) Assessing the effects of LXR agonists on cellular cholesterol handling: a stable isotope tracer study. J Lipid Res 47:1250–1260

    Article  CAS  PubMed  Google Scholar 

  • Bai X, Hong W, Cai P, Chen Y, Xu C, Cao D, Yu W, Zhao Z, Huang M, Jin J (2017) Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis. Toxicol Appl Pharmacol 324:12–25

    Article  CAS  PubMed  Google Scholar 

  • Barbara BG, DiPiro JT, Schwinghammer TL (2012) Pharmacotherapy handbook, 9th edn. The McGraw-Hill Companies, Inc, New York

    Google Scholar 

  • Brinton EA (2003) Lipid abnormalities in the metabolic syndrome. Curr Diab Rep 3:65–72

    Article  PubMed  Google Scholar 

  • Chang YH, Ho WC, Tsai JJ, Li CY, Lu TH (2012) Risk of mortality among patients with epilepsy in southern Taiwan. Seizure 21:254–259

    Article  PubMed  Google Scholar 

  • Changchien CS, Wang JH, Tsai TL, Hung CH (2003) Correlation between fatty liver and lipidemia in Taiwanese. J Med Ultrasound 11:60–65

    Article  Google Scholar 

  • Chateauvieux S, Morceau F, Dicato M, Diederich M (2010) Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol 2010:479364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng LS, Prasad AN, Rieder MJ (2010) Relationship between antiepileptic drugs and biological markers affecting long-term cardiovascular function in children and adolescents. Can J Clin Pharmacol 17:e5–e46

    PubMed  Google Scholar 

  • Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML (2011) Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 20:236–242

    Article  PubMed  Google Scholar 

  • Chuang YC, Chuang HY, Lin TK, Chang CC, Lu CH, Chang WN, Chen SD, Tan TY, Huang CR, Chan SH (2012) Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia 53:120–128

    Article  CAS  PubMed  Google Scholar 

  • Eirís JM, Lojo S, Del Río MC, Novo I, Bravo M, Pavón P, Castro-Gago M (1995) Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 45:1155–1157

    Article  PubMed  Google Scholar 

  • Farinelli E, Giampaoli D, Cenciarini A, Cercado E, Verrotti A (2015) Valproic acid and nonalcoholic fatty liver disease: a possible association? World J Hepatol 7:1251–1257

    Article  PubMed  PubMed Central  Google Scholar 

  • Fernández-Alvarez A, Alvarez MS, Gonzalez R, Cucarella C, Muntané J, Casado M (2011) Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 286:21466–21477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferré P, Foufelle F (2007) SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68:72–82

    PubMed  Google Scholar 

  • Gram L, Bentsen KD (1983) Hepatic toxicity of antiepileptic drugs: a review. Acta Neurol Scand Suppl 97:81–90

    Article  CAS  PubMed  Google 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 277:34182–34190

    Article  CAS  PubMed  Google Scholar 

  • Hamed SA, Hamed EA, Kandil MR, El-Shereef HK, Abdellah MM, Omar H (2005) Serum thyroid hormone balance and lipid profile in patients with epilepsy. Epilepsy Res 66:173–183

    Article  CAS  PubMed  Google Scholar 

  • Hansen J, Åsberg S, Kumlien E, Zelano J (2017) Cause of death in patients with poststroke epilepsy: results from a nationwide cohort study. PLoS One 12:e0174659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harnod T, Chen HJ, Li TC, Sung FC, Kao CH (2014) A high risk of hyperlipidemia in epilepsy patients: a nationwide population-based cohort study. Ann Epidemiol 24:910–914

    Article  PubMed  Google Scholar 

  • Higuchi N, Kato M, Shundo Y, Tajiri H, Tanaka M, Yamashita N, Kohjima M, Kotoh K, Nakamuta M, Takayanagi R, Enjoji M (2008) Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res 38:1122–1129

    Article  CAS  PubMed  Google Scholar 

  • Hsieh LP, Huang CY (2009) Antiepileptic drug utilization in Taiwan: analysis of prescription using National Health Insurance database. Epilepsy Res 84:21–27

    Article  PubMed  Google Scholar 

  • Janszky I, Hallqvist J, Tomson T, Ahlbom A, Mukamal KJ, Ahnve S (2009) Increased risk and worse prognosis of myocardial infarction in patients with prior hospitalization for epilepsy—the Stockholm Heart Epidemiology Program. Brain 132:2798–2804

    Article  PubMed  Google Scholar 

  • Jetter GM, Cavazos JE (2008) Epilepsy in the elderly. Semin Neurol 28:336–341

    Article  PubMed  Google Scholar 

  • Ji Q, Shi X, Lin R, Mao Y, Zhai X, Lin Q, Zhang J (2010) Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells. Toxicol In Vitro 24:1086–1091

    Article  CAS  PubMed  Google Scholar 

  • Kase ET, Wensaas AJ, Aas V, Højlund K, Levin K, Thoresen GH, Beck-Nielsen H, Rustan AC, Gaster M (2005) Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes 54:1108–1115

    Article  CAS  PubMed  Google Scholar 

  • Knebel B, Haas J, Hartwig S, Jacob S, Köllmer C, Nitzgen U, Muller-Wieland D, Kotzka J (2012) Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS One 7:e31812

    Article  CAS  PubMed  PubMed Central  Google 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 85:1526–1527

    Article  PubMed  Google Scholar 

  • Lai SW, Tan CK, Ng KC (2002) Epidemiology of fatty liver in a hospital-based study in Taiwan. South Med J 95:1288–1292

    Article  PubMed  Google Scholar 

  • Lee MH, Kim M, Lee BH, Kim JH, Kang KS, Kim HL, Yoon BI, Chung H, Kong G, Lee MO (2008) Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver. Toxicol Appl Pharmacol 226:271–284

    Article  CAS  PubMed  Google Scholar 

  • Leonardi M, Ustun TB (2002) The global burden of epilepsy. Epilepsia 43(Suppl 6):21–25

    Google 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 86:42–47

    Article  CAS  PubMed  Google Scholar 

  • Manimekalai K, Visakan B, Salwe KJ, Murugesan S (2014) Evluation of effect of antiepileptic drugs on serum lipid profile among young adults with epilepsy in a tertiary care hospital in Pondicherry. J Clin Diagn Res 8:HC05–HC09

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mantel-Teeuwisse AK, Kloosterman JM, Maitland-van der Zee AH, Klungel OH, Porsius AJ, de Boer A (2001) Drug-induced lipid changes: a review of the unintended effects of some commonly used drugs on serum lipid levels. Drug Saf 24:443–456

    Article  CAS  PubMed  Google Scholar 

  • National Health Insurance Research Database, Taiwan. http://nhird.nhri.org.tw/en/index.htm (cited in 2016)

  • Ratni H, Wright MB (2010) Recent progress in liver X receptor-selective modulators. Curr Opin Drug Discov Devel 13:403–413

    CAS  PubMed  Google Scholar 

  • 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 14:2819–2830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmid MM, Freudenmann RW, Keller F, Connemann BJ, Hiemke C, Gahr M, Kratzer W, Fuchs M, Schönfeldt-Lecuona C (2013) Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry 46:63–68

    CAS  PubMed  Google Scholar 

  • Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (2000) Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith D, Chadwick D (2001) The management of epilepsy. J Neurol Neurosurg Psychiatry 70(Suppl 2):II15–II21

    PubMed  PubMed Central  Google Scholar 

  • Sonmez FM, Demir E, Orem A, Yildirmis S, Orhan F, Aslan A, Topbas M (2006) Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes. J Child Neurol 21:70–74

    Article  PubMed  Google Scholar 

  • Tice CM, Noto PB, Fan KY, Zhuang L, Lala DS, Singh SB (2014) The medicinal chemistry of liver X receptor (LXR) modulators. J Med Chem 57:7182–7205

    Article  CAS  PubMed  Google Scholar 

  • Tsiropoulos I, Andersen M, Hallas J (2009) Adverse events with use of antiepileptic drugs: a prescription and event symmetry analysis. Pharmacoepidemiol Drug Saf 18:483–491

    Article  CAS  PubMed  Google Scholar 

  • Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA (2000) Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275:14700–14707

    Article  CAS  PubMed  Google Scholar 

  • Vyas MV, Davidson BA, Escalaya L, Costella J, Saposnik G, Burneo JG (2015) Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review. Epilepsy Res 113:44–67

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Lin R, Zhang J, Mao Y, Bu X, Ji Q, Zhai X, Lin Q, Yang L, Zhang K (2012) Involvement of fatty acid metabolism in the hepatotoxicity induced by divalproex sodium. Hum Exp Toxicol 31:1092–1101

    Article  CAS  PubMed  Google Scholar 

  • Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:1033–1045

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Robertson DH, Brooks CL, Vieth M (2003) Detailed analysis of grid-based molecular docking: a case study of CDOCKER-A CHARMm-based MD docking algorithm. J Comput Chem 24:1549–1562

    Article  CAS  PubMed  Google Scholar 

Download references

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 information

Author notes

  1. Yi-Wen Li and Chung-Hsing Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan, Republic of China

    Yi-Wen Li, Wai-Kok Cheng, Hsin-Yi Shen & Yun-Ping Lim

  2. Children’s Hospital of China Medical University, Taichung, Taiwan, ROC

    Chung-Hsing Wang

  3. Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC

    Chao-Jung Chen

  4. Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC

    Chao-Jung Chen

  5. Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, ROC

    Charles C. N. Wang

  6. Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, ROC

    Cheng-Li Lin

  7. Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC

    Yun-Ping Lim

  8. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC

    Yun-Ping Lim

Authors
  1. Yi-Wen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chung-Hsing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao-Jung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles C. N. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng-Li Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wai-Kok Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hsin-Yi Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun-Ping Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Chao-Jung Chen or Yun-Ping Lim.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1031 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, YW., Wang, CH., Chen, CJ. et al. Effects of antiepileptic drugs on lipogenic gene regulation and hyperlipidemia risk in Taiwan: a nationwide population-based cohort study and supporting in vitro studies. Arch Toxicol 92, 2829–2844 (2018). https://doi.org/10.1007/s00204-018-2263-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-018-2263-3

Keywords

Search

Navigation