Skip to main content
SpringerLink
Log in

SREBP Activation by Antipsychotic- and Antidepressant-Drugs in Cultured Human Liver Cells: Relevance for Metabolic Side-Effects?

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Drug-induced weight gain is a major problem in the treatment of psychiatric disorders, especially with some antipsychotic- and antidepressant drugs. We have recently demonstrated that antipsychotic- and antidepressant drugs activate the SREBP (sterol regulatory element-binding proteins) transcription factors in human- and rat glial cells, with subsequent up-regulation of downstream genes involved in cholesterol- and fatty acid biosynthesis. Since stimulation of cellular lipogenesis in the liver could be of relevance for the metabolic side effects of these drugs, we have now investigated the effects of antidepressants, antipsychotic- and mood-stabilizing drugs on cell cultures of human liver cells. For several of the drugs being strongly associated with weight gain (clozapine, imipramine, and amitriptyline), we observed a very pronounced activation of SREBP. Ziprasidone and buproprion, however, which are not associated with weight gain, did hardly stimulate the SREBP system. For haloperidol, olanzapine and mirtazapine, the correspondence between metabolic side effects and SREBP stimulation in liver cells was less obvious. The mood-stabilizers did not increase SREBP activation. The results indicate a relationship between drug-induced activation of SREBP in cultured human liver cells and weight gain side-effects of antidepressant and antipsychotic drugs.

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

Similar content being viewed by others

References

  1. Zimmermann U, Kraus T, Himmerich H, Schuld A, Pollmacher T: Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res 37: 193–220, 2003

    Article  PubMed  Google Scholar 

  2. Melkersson K, Dahl ML: Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications. Drugs 64: 701–723, 2004

    Article  PubMed  CAS  Google Scholar 

  3. Antoine MH, Gall D, Schiffmann SN, Lebrun P: Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action. Diabetologia 47: 909–916, 2004

    Article  PubMed  CAS  Google Scholar 

  4. List JF, Habener JF: Defective melanocortin 4 receptors in hyperphagia and morbid obesity. N Engl J Med 348: 1160–1163, 2003

    Article  PubMed  Google Scholar 

  5. Raeder MB, Ferno J, Glambek M, Stansberg C, Steen VM: Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. Neurosci Lett 395: 185–190, 2006

    Article  PubMed  CAS  Google Scholar 

  6. Ferno J, Raeder MB, Vik-Mo AO, Skrede S, Glambek M, Tronstad KJ, Breilid H, Lovlie R, Berge RK, Stansberg C, Steen VM: Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? Pharmacogenomics J 5: 298–304, 2005

    Google Scholar 

  7. Horton JD, Goldstein JL, Brown MS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109: 1125–1131, 2002

    Article  PubMed  CAS  Google Scholar 

  8. Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn CR: Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Diabetes 54: 1314–1323, 2005

    PubMed  CAS  Google Scholar 

  9. Casey DE, Haupt DW, Newcomer JW, Henderson DC, Sernyak MJ, Davidson M, Lindenmayer JP, Manoukian SV, Banerji MA, Lebovitz HE, Hennekens CH: Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry 65 Suppl 7: 4–18; quiz 19–20, 2004

    Google Scholar 

  10. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156: 1686–1696, 1999

    PubMed  CAS  Google Scholar 

  11. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353: 1209–1223, 2005

    Article  PubMed  CAS  Google Scholar 

  12. Keck PE, McElroy SL: Bipolar disorder, obesity, and pharmacotherapy-associated weight gain. J Clin Psychiatry 64: 1426–1435, 2003

    PubMed  Google Scholar 

  13. Pfeifer AM, Cole KE, Smoot DT, Weston A, Groopman JD, Shields PG, Vignaud JM, Juillerat M, Lipsky MM, Trump BF, et al.: Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci U S A 90: 5123–5127, 1993

    Article  PubMed  CAS  ADS  Google Scholar 

  14. Budavari S, O'eil M, Smith A, Heckelman P and Kinneary Je: The Merck Index. An encyclopedia of chemicals, drugs and biologicals. Merck, Rahway, New Jersey 12th edn: 411–1170, 1996

  15. Schmider J, von Moltke LL, Shader RI, Harmatz JS, Greenblatt DJ: Extrapolating in vitro data on drug metabolism to in vivo pharmacokinetics: evaluation of the pharmacokinetic interaction between amitriptyline and fluoxetine. Drug Metab Rev 31: 545–560, 1999

    Article  PubMed  CAS  Google Scholar 

  16. Hardman J, Limbird L, Gilman A: Goodman & Gilmanapos; The Pharmacological Basis of Therapeutics, 10th eds. McGraw-Hill, New York, 2001

  17. Baselt R, Cravey RH and eds.: Clozapine. In: Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA: Chemical Toxicology Institute: 184–184, 1995

  18. Horton JD, Shimomura I, Brown MS, Hammer RE, Goldstein JL, Shimano H: Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J Clin Invest 101: 2331–2339, 1998

    PubMed  CAS  Google Scholar 

  19. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL: Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98: 1575–1584, 1996

    Article  PubMed  CAS  Google Scholar 

  20. Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL: Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99: 846–854, 1997

    PubMed  CAS  Google Scholar 

  21. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS: Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12: 3182–3194, 1998

    PubMed  CAS  Google Scholar 

  22. Laudes M, Barroso I, Luan J, Soos MA, Yeo G, Meirhaeghe A, Logie L, Vidal-Puig A, Schafer AJ, Wareham NJ, O'ahilly S: Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes. Diabetes 53: 842–846, 2004

    PubMed  CAS  Google Scholar 

  23. Eberle D, Clement K, Meyre D, Sahbatou M, Vaxillaire M, Le Gall A, Ferre P, Basdevant A, Froguel P, Foufelle F: SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts. Diabetes 53: 2153–2157, 2004

    PubMed  CAS  Google Scholar 

  24. Vedie B, Jeunemaitre X, Megnien JL, Atger V, Simon A, Moatti N: A new DNA polymorphism in the 5’ untranslated region of the human SREBP-1a is related to development of atherosclerosis in high cardiovascular risk population. Atherosclerosis 154: 589–597, 2001

    Article  PubMed  CAS  Google Scholar 

  25. Miserez AR, Muller PY, Barella L, Barella S, Staehelin HB, Leitersdorf E, Kark JD, Friedlander Y: Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia. Atherosclerosis 164: 15–26, 2002

    Article  PubMed  CAS  Google Scholar 

  26. Nicholas LM, Ford AL, Esposito SM, Ekstrom RD Golden RN: The effects of mirtazapine on plasma lipid profiles in healthy subjects. J Clin Psychiatry 64: 883–889, 2003

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse, Bergen HF, N-5021, Norway

    Maria B. Raeder, Johan Fernø, Audun O. Vik-Mo & Vidar M. Steen

  2. Dr. Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health, Research Center, Section for Medical Genetics and Molecular Medicine, University of Bergen, Bergen, Norway

    Maria B. Raeder, Johan Fernø, Audun O. Vik-Mo & Vidar M. Steen

Authors
  1. Maria B. Raeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johan Fernø
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Audun O. Vik-Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vidar M. Steen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria B. Raeder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raeder, M.B., Fernø, J., Vik-Mo, A.O. et al. SREBP Activation by Antipsychotic- and Antidepressant-Drugs in Cultured Human Liver Cells: Relevance for Metabolic Side-Effects?. Mol Cell Biochem 289, 167–173 (2006). https://doi.org/10.1007/s11010-006-9160-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9160-4

Key words

Search

Navigation