Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?
作者： J Fernø , M B Raeder , A O Vik-Mo , S Skrede , M Glambek
关键词:
摘要: 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 synaptogenesis the CNS. Lipogenesis myelin synthesis are thus interesting etiological candidate targets schizophrenia. Using a microarray approach, we here demonstrate that antipsychotic drugs clozapine haloperidol upregulate several genes involved fatty acid biosynthesis cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 synthase-1), FASN (fatty synthase) SCD (stearoyl-CoA desaturase). The changes gene expression were followed by enhanced HMGCR-enzyme activity elevated cellular levels of triglycerides. upregulated all known to be controlled sterol regulatory element-binding protein (SREBP) transcription factors. We show activate SREBP system. antipsychotic-induced SREBP-mediated increase glial cell lipogenesis could represent novel mechanism action, may also relevant metabolic side effects antipsychotics.
nature.com
sci-hub.se 参考文章(42)
Daniel E Casey, Dan W Haupt, John W Newcomer, David C Henderson, Michael J Sernyak, Michael Davidson, Jean-Pierre Lindenmayer, Steven V Manoukian, Mary Ann Banerji, Harold E Lebovitz, Charles H Hennekens, Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. The Journal of Clinical Psychiatry. ,vol. 65, pp. 4- 18 ,(2004) , 10.4088/JCP.V65N0101
Arun Radhakrishnan, Li-Ping Sun, Hyock Joo Kwon, Michael S Brown, Joseph L Goldstein, Direct Binding of Cholesterol to the Purified Membrane Region of SCAP: Mechanism for a Sterol-Sensing Domain Molecular Cell. ,vol. 15, pp. 259- 268 ,(2004) , 10.1016/J.MOLCEL.2004.06.019
M S Brown, J L Goldstein, J M Dietschy, 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. Journal of Biological Chemistry. ,vol. 254, pp. 5144- 5149 ,(1979) , 10.1016/S0021-9258(18)50571-8
Robert B. Rawson, The SREBP pathway--insights from Insigs and insects. Nature Reviews Molecular Cell Biology. ,vol. 4, pp. 631- 640 ,(2003) , 10.1038/NRM1174
Yvonne Lange, Theodore L Steck, Cholesterol homeostasis. Modulation by amphiphiles. Journal of Biological Chemistry. ,vol. 269, pp. 29371- 29374 ,(1994) , 10.1016/S0021-9258(18)43886-0
Gene C. Ness, Developmental regulation of the expression of genes encoding proteins involved in cholesterol homeostasis American Journal of Medical Genetics. ,vol. 50, pp. 355- 357 ,(1994) , 10.1002/AJMG.1320500411
H. Nasrallah, A review of the effect of atypical antipsychotics on weight Psychoneuroendocrinology. ,vol. 28, pp. 83- 96 ,(2003) , 10.1016/S0306-4530(02)00114-2
Andrea Schmitt, Katrin Wilczek, Kaj Blennow, Athanasios Maras, Alexander Jatzko, Georg Petroianu, Dieter F Braus, Wagner F Gattaz, Altered thalamic membrane phospholipids in schizophrenia: a postmortem study Biological Psychiatry. ,vol. 56, pp. 41- 45 ,(2004) , 10.1016/J.BIOPSYCH.2004.03.019
D. H. Mauch, CNS Synaptogenesis Promoted by Glia-Derived Cholesterol Science. ,vol. 294, pp. 1354- 1357 ,(2001) , 10.1126/SCIENCE.294.5545.1354
Michael D. Nelson, Andrew J. Saykin, Laura A. Flashman, Henry J. Riordan, Hippocampal Volume Reduction in Schizophrenia as Assessed by Magnetic Resonance Imaging Archives of General Psychiatry. ,vol. 55, pp. 433- 440 ,(1998) , 10.1001/ARCHPSYC.55.5.433