Department of Biosciences, Biotechnology and Pharmacological Sciences, University of Bari, Via Orabona 4, 70125 Bari, Italy.
Eur Neuropsychopharmacol. 2013 Aug;23(8):978-87. doi: 10.1016/j.euroneuro.2012.08.015. Epub 2012 Sep 7.
The use of clozapine and other antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function and abnormal insulin secretion, although the underlying mechanisms are unknown. The aim of this study is the identification of targets for clozapine related to the abnormal insulin secretion. We identify a specific activation of the transcriptional factor FOXA1, but not FOXA2 and FOXA3, by clozapine in HepG2 cells. Clozapine enhances FOXA1 DNA-binding and its transcriptional activity, increasing mitochondrial citrate carrier gene expression, which contains a FOXA1 site in its promoter. Haloperidol, a conventional antipsychotic drug, does not determine any increase of FOXA1 gene expression. We also demonstrate that clozapine upregulates FOXA1 and CIC gene expression in INS-1 cells only at basal glucose concentration. In addition, we find that abnormal insulin secretion in basal glucose conditions could be completely abolished by FOXA1 silencing in INS-1 cells treated with clozapine. The identification of FOXA1 as a novel target for clozapine may shed more light to understand molecular mechanism of abnormal insulin secretion during clozapine treatment.
氯氮平及其他抗精神病药物的使用已知与许多不良代谢副作用有关，包括糖尿病。这些副作用至少部分可能是胰岛细胞功能障碍和胰岛素分泌异常的结果，尽管其潜在机制尚不清楚。本研究旨在确定与异常胰岛素分泌有关的氯氮平相关靶点。我们发现氯氮平在 HepG2 细胞中特异性激活转录因子 FOXA1，但不激活 FOXA2 和 FOXA3。氯氮平增强 FOXA1 的 DNA 结合及其转录活性，增加含有启动子中 FOXA1 位点的线粒体柠檬酸载体基因的表达。氟哌啶醇，一种传统的抗精神病药物，不会导致 FOXA1 基因表达的任何增加。我们还证明，氯氮平仅在基础葡萄糖浓度下上调 INS-1 细胞中的 FOXA1 和 CIC 基因表达。此外，我们发现氯氮平处理的 INS-1 细胞中，FOXA1 沉默可完全消除基础葡萄糖条件下的异常胰岛素分泌。FOXA1 作为氯氮平的新型靶点的鉴定，可能有助于更深入地了解氯氮平治疗期间异常胰岛素分泌的分子机制。
