Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?
Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?
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DOI：
10.1038/sj.tpj.6500323
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发表时间：
2005-10-01
影响因子：
2.8
通讯作者：
Steen, VM
中科院分区：
文献类型：
--
作者：
Ferno, J;Raeder, MB;Steen, VM
一些研究报道了精神分裂症患者死后大脑的结构异常、髓鞘形成减少和少突胶质细胞功能障碍。神经胶质源性胆固醇对中枢神经系统中的髓鞘形成和突触形成都是必不可少的。因此，脂肪生成和髓鞘合成是精神分裂症的有趣的病因学候选目标。使用微阵列的方法，我们在这里证明，抗精神病药物氯氮平和氟哌啶醇上调几个基因参与胆固醇和脂肪酸的生物合成在培养的人类胶质瘤细胞，包括HMGCR（3-羟基-3-甲基戊二酰-辅酶A还原酶），HMGCS 1（3-羟基-3-甲基戊二酰-辅酶A合酶-1）、脂肪酸合酶（Fatty acid synthase）和SCD（stearoyl- CoA desaturase）。基因表达的变化之后是增强的HMGCR酶活性和升高的细胞胆固醇和甘油三酯水平。已知上调的基因都是由固醇调节元件结合蛋白（SREBP）转录因子控制的。我们发现，氯氮平和氟哌啶醇都激活SREBP系统。抗精神病药诱导的SREBP介导的胶质细胞脂肪生成增加可能代表了一种新的作用机制，也可能与抗精神病药的代谢副作用有关。
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.