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Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

The Pharmacogenomics Journal volume 5, pages 298–304 (2005)Cite this article

Abstract

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.

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References

  1. Freedman R . Schizophrenia. N Engl J Med 2003; 349: 1738–1749.

    Article  CAS  PubMed  Google Scholar 

  2. Mueser KT, McGurk SR . Schizophrenia. Lancet 2004; 363: 2063–2072.

    Article  PubMed  Google Scholar 

  3. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68.

    Article  CAS  PubMed  Google Scholar 

  4. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ . Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 1998; 55: 433–440.

    Article  CAS  PubMed  Google Scholar 

  5. Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET . Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157: 16–25.

    Article  CAS  PubMed  Google Scholar 

  6. Zipursky RB, Lambe EK, Kapur S, Mikulis DJ . Cerebral gray matter volume deficits in first episode psychosis. Arch Gen Psychiatry 1998; 55: 540–546.

    Article  CAS  PubMed  Google Scholar 

  7. Szeszko PR, Goldberg E, Gunduz-Bruce H, Ashtari M, Robinson D, Malhotra AK et al. Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia. Am J Psychiatry 2003; 160: 2190–2197.

    Article  PubMed  Google Scholar 

  8. Kasai K, Shenton ME, Salisbury DF, Hirayasu Y, Onitsuka T, Spencer MH et al. Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2003; 60: 766–775.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Harrison P, Lewis DA . Neuropathology of schizophrenia. In: Hirsch S, Weinberger DR (eds). Schizophrenia, 2nd edn. Blackwell Science: Oxford, UK, 2003 pp. 310–325.

    Chapter  Google Scholar 

  10. Liddle P, Pantelis C . Brain imaging in schizophrenia. In: Hirsch S, Weinberger DR (eds). Schizophrenia, 2nd edn. Blackwell Science: Oxford, UK, 2003 pp. 403–417.

    Chapter  Google Scholar 

  11. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003; 362: 798–805.

    Article  CAS  PubMed  Google Scholar 

  13. Aston C, Jiang L, Sokolov BP . Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res 2004; 77: 858–866.

    Article  CAS  PubMed  Google Scholar 

  14. Schmitt A, Wilczek K, Blennow K, Maras A, Jatzko A, Petroianu G et al. Altered thalamic membrane phospholipids in schizophrenia: a postmortem study. Biol Psychiatry 2004; 56: 41–45.

    Article  CAS  PubMed  Google Scholar 

  15. Dietschy JM, Turley SD . Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004; 45: 1375–1397.

    Article  CAS  PubMed  Google Scholar 

  16. Ness GC . Developmental regulation of the expression of genes encoding proteins involved in cholesterol homeostasis. Am J Med Genet 1994; 50: 355–357.

    Article  CAS  PubMed  Google Scholar 

  17. Verheijen MH, Chrast R, Burrola P, Lemke G . Local regulation of fat metabolism in peripheral nerves. Genes Dev 2003; 17: 2450–2464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001; 294: 1354–1357.

    Article  CAS  PubMed  Google Scholar 

  19. Koudinov AR, Koudinova NV . Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 2001; 15: 1858–1860.

    Article  CAS  PubMed  Google Scholar 

  20. Hayashi H, Campenot RB, Vance DE, Vance JE . Glial lipoproteins stimulate axon growth of central nervous system neurons in compartmented cultures. J Biol Chem 2004; 279: 14009–14015.

    Article  CAS  PubMed  Google Scholar 

  21. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 2003; 60: 443–456.

    Article  PubMed  Google Scholar 

  22. Miyamoto S, Duncan GE, Marx CE, Lieberman JA . Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79–104.

    Article  CAS  PubMed  Google Scholar 

  23. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B . Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518–526.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Nasrallah H . A review of the effect of atypical antipsychotics on weight. Psychoneuroendocrinology 2003; 28 (Suppl 1): 83–96.

    Article  CAS  PubMed  Google Scholar 

  26. Casey DE, Haupt DW, Newcomer JW, Henderson DC, Sernyak MJ, Davidson M et al. Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry 2004; 65 (Suppl 7): 4–18, (quiz 19–20).

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Akslen LA, Andersen KJ, Bjerkvig R . Characteristics of human and rat glioma cells grown in a defined medium. Anticancer Res 1988; 8: 797–803.

    CAS  PubMed  Google Scholar 

  29. Brown MS, Goldstein JL, Dietschy JM . Active and inactive forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of the rat. Comparison with the rate of cholesterol synthesis in different physiological states. J Biol Chem 1979; 254: 5144–5149.

    CAS  PubMed  Google Scholar 

  30. Shimano H . Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001; 40: 439–452.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rawson RB . The SREBP pathway—insights from Insigs and insects. Nat Rev Mol Cell Biol 2003; 4: 631–640.

    Article  CAS  PubMed  Google Scholar 

  33. Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS . Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 1997; 99: 838–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Salles J, Sargueil F, Knoll-Gellida A, Witters LA, Cassagne C, Garbay B . Acetyl-CoA carboxylase and SREBP expression during peripheral nervous system myelination. Biochim Biophys Acta 2003; 1631: 229–238.

    Article  CAS  PubMed  Google Scholar 

  35. Lange Y, Steck TL . Cholesterol homeostasis. Modulation by amphiphiles. J Biol Chem 1994; 269: 29371–29374.

    CAS  PubMed  Google Scholar 

  36. Lange Y, Ye J, Rigney M, Steck TL . Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol. J Lipid Res 1999; 40: 2264–2270.

    CAS  PubMed  Google Scholar 

  37. Adams CM, Goldstein JL, Brown MS . Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc Natl Acad Sci USA 2003; 100: 10647–10652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL . Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell 2004; 15: 259–268.

    Article  CAS  PubMed  Google Scholar 

  39. Thomas EA, George RC, Danielson PE, Nelson PA, Warren AJ, Lo D et al. Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol Psychiatry 2003; 8: 983–993, 950.

    Article  CAS  PubMed  Google Scholar 

  40. Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiatry 2000; 57: 471–480.

    Article  CAS  PubMed  Google Scholar 

  41. Sigmundsson T, Suckling J, Maier M, Williams S, Bullmore E, Greenwood K et al. Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. Am J Psychiatry 2001; 158: 234–243.

    Article  CAS  PubMed  Google Scholar 

  42. Finelli PF . Metachromatic leukodystrophy manifesting as a schizophrenic disorder: computed tomographic correlation. Ann Neurol 1985; 18: 94–95.

    Article  CAS  PubMed  Google Scholar 

  43. Hyde TM, Ziegler JC, Weinberger DR . Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992; 49: 401–406.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the research infrastructure provided by the Norwegian Microarray Consortium, a national FUGE technology platform (Functional Genomics in Norway). The present study has been supported by grants from the Research Council of Norway (incl. the FUGE programme, ‘Senter for grunnleggende sykdomsmekanismer’ and Mental Health programme), Helse Vest RHF and Dr Einar Martens Fund.

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Authors and Affiliations

  1. 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

    J Fernø, M B Raeder, A O Vik-Mo, S Skrede, M Glambek, H Breilid, R Løvlie, C Stansberg & V M Steen

  2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen, HF, Norway

    J Fernø, M B Raeder, A O Vik-Mo, S Skrede, M Glambek, H Breilid, R Løvlie, C Stansberg & V M Steen

  3. Section of Medical Biochemistry, Institute of Medicine, University of Bergen, Norway

    K-J Tronstad & R K Berge

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  1. J Fernø
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Fernø, J., Raeder, M., Vik-Mo, A. et al. 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). https://doi.org/10.1038/sj.tpj.6500323

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