- 學位論文
Olanzapine促進細胞脂質新生的機轉探討
The mechanism of lipogenesis enhanced by olanzapine in cell lines
摘要
非典型抗精神病藥olanzapine為臨床上第一線的精神疾病用藥，目前被廣泛使用於治療躁症、鬱症等精神疾病。最主要的副作用為體重增加與血脂上升，造成病人順從性的降低與新血管疾病的危險性升高。目前通泛的解釋為阻斷5-HT2C、H1與促進5-HT1A受體引起的食量增加，但是詳細的機轉目前仍不清楚。本實驗利用3T3-L1前驅脂肪細胞分化的模式觀察到olanzapine可以加強細胞內三酸甘油脂的蓄積，並且增加fatty acid synthase與adiponectin的mRNA表現，機轉上可能是透過SREBP-1轉錄因子。利用報導基因的研究發現olanzapine除了能增加SREBP-1對於含有SRE-1 promoter的基因的轉錄能力外，也促進了SREBP-1的表現。在HepG2 肝細胞株上，也證明了olanzapine可以促進報導基因與SREBP-1的表現。本實驗結果發現olanzapine除了中樞神經的作用外，亦可能透過SREBP-1在脂細胞及肝細胞影響體內脂質的合成。
並列摘要
Olanzapine is a second generation atypical antipsychotic drug, treating positive symptom, negative symptom, etc. The major side effects are weight gain and hyperglycemia. These effects reduce patient compliance and are risk factors of cardiac vascular disease. The possible mechanisms are poor satiety and increases in food intake induced by 5-HT2C, H1 receptor antagonists and 5-H1A agonists; the exact mechanisms are still unclear. In the present study, we observed olanzapine increased triacylglyceride (TG) accumulation during 3T3-L1 preadipocyte differentiation, as well as the expression of fatty acid synthase and adiponectin. The effect may be regulated by SREBP-1, a major transcription factor in lipid homeostasis. Olanzapine enhances the activity of SRE-1-containing LDLR promoter in tranfected 3T3-L1 preadipocyte and HepG2 cell lines. Increase in SREBP-1 precursor form was as well observed. In conclusion, olanzapine may not only cause adiposity through CNS receptor, but also affect the peripheral lipogenic molecules regulated by SREBP-1.