PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients
PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients
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PCSK9介导奥氮平治疗精神分裂症患者诱发的血脂异常
DOI：
10.1007/s00213-021-06042-z
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发表时间：
2022-01-14
影响因子：
3.4
通讯作者：
Wu, Renrong
中科院分区：
文献类型：
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作者：
Huang, Jing;Xiao, Jingmei;Wu, Renrong
精神分裂症患者抗精神病药物引起的血脂异常是由于体重增加还是药物治疗的直接影响，目前还存在争议。目的探讨前蛋白转化酶枯草杆菌蛋白酶9（PCSK 9）在奥氮平诱导的血脂异常中的作用，为临床应用提供理论依据。我们分析了精神分裂症患者和涉及小鼠和细胞的实验模型，以了解其机制。在首发精神分裂症患者中前瞻性评估了奥氮平治疗周。此外，小鼠奥氮平给药5或8周，描绘肝PCSK 9的行动有助于奥氮平诱导dyslipidemi.ResultsOlanzapine直接影响脂质代谢，这表明血脂异常是独立的体重增加精神分裂症患者。奥氮平给药后血浆PCSK 9明显升高，且与低密度脂蛋白胆固醇（LDL-C）升高呈正相关（r= 0.77，p <0.001）。在奥氮平诱导的LDL-C异常之前，奥氮平处理小鼠肝组织中PCSK 9表达增加。在奥氮平处理的小鼠中，肝固醇调节元件结合蛋白-2（SREBP-2）蛋白水平升高，但在奥氮平（10μM）处理的HepG 2细胞中，该蛋白水平大幅下降，这表明高浓度奥氮平诱导的PCSK 9升高不是SREBP-2依赖性的。然而，在较高剂量给药组中，固醇调节元件结合蛋白-1c（SREBP-1c）的表达显著增加，这与PCSK 9增加一致。高剂量奥氮平治疗后SREBP-1c的激活促进PSCK 9的表达，因此低密度脂蛋白受体的降解导致LDL-C increase.ConclusionsLipid disturbances caused by olanzapine are independent of weight gain.本研究探讨了SREBP-1c和PCSK 9在体内外奥氮平治疗后调节脂蛋白代谢中的关系。进一步探索奥氮平诱导的PCSK 9调节机制可能有助于确定抑制奥氮平介导的血脂异常的控制点。
RationaleIt is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear.ObjectiveTo study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism.MethodsDisturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia.ResultsOlanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77,p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10μM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase.ConclusionsLipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.