Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs.
Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs.
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DOI：
10.1186/1471-2202-7-69
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发表时间：
2006-10-20
期刊：
影响因子：
2.4
通讯作者：
Steen VM
中科院分区：
文献类型：
--
作者：
Fernø J;Skrede S;Vik-Mo AO;Håvik B;Steen VM
精神分裂症的病因尚不清楚，但神经发育障碍、髓鞘和少突胶质细胞异常以及突触功能障碍被认为是这种严重精神疾病的病理生理因素。胆固醇是髓鞘的基本成分，已被证明对突触的形成很重要。最近，我们证明了抗精神病药物氯氮平和氟哌啶醇通过激活固醇调节元件结合蛋白(SREBP)转录因子来刺激培养的胶质瘤细胞的造脂基因表达。我们比较了氯丙嗪、氟哌啶醇、氯氮平、奥氮平、利培酮和齐拉西酮对四种中枢神经系统相关细胞系SREBP激活和SREBP调控基因(ACAT2、HMGCR、HMGCS1、FDPS、SC5DL、DHCR7、LDLR、FASN和SCD1)表达的影响。在抗精神病药物激活SREBP靶基因表达的能力方面存在显著差异，在治疗相关浓度的背景下，氯氮平和氯丙嗪是最有效的刺激剂。胶质样细胞(GAMG胶质瘤和CCF-STTG1星形细胞瘤细胞株)在药物诱导的SREBP激活方面表现出比在HCN2人皮质神经元和SH-SY5Y神经母细胞瘤细胞中更明显的激活，这表明抗精神病药物诱导的脂肪生成的激活在胶质细胞中最为显著。我们目前的数据显示，在培养的人类中枢神经系统相关细胞中，不同的抗精神病药物诱导SREBP控制的脂肪生成转录激活的能力存在显着差异。我们认为这一效应可能与某些抗精神病药物的疗效有关。
The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP) transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1) in four CNS-relevant human cell lines. There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines) displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.
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DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
作者：
Horton, JD;Bashmakov, Y;Shimano, H
通讯作者：
Shimano, H
影响因子：
2.8
作者：
Ferno, J;Raeder, MB;Steen, VM
通讯作者：
Steen, VM
DOI：
10.1073/pnas.1534923100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Horton, JD;Shah, NA;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
4.8
作者：
Janowski, BA;Shan, B;Russell, DW
通讯作者：
Russell, DW
影响因子：
17.7
作者：
Kornhuber, J;Schultz, A;Riederer, P
通讯作者：
Riederer, P