Huang Piao-Piao, Zhu Wen-Qiang, Xiao Jing-Mei, Zhang Yi-Qi, Li Rong, Yang Yang, Shen Li, Luo Fei, Dai Wen, Lian Ping-An, Tang Ya-Xin, Ran Juan-Li, Huang Xian-Sheng
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Research Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Front Pharmacol. 2022 Aug 12;13:935362. doi: 10.3389/fphar.2022.935362. eCollection 2022.
Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic mRNA. Consistently, studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein , without effects on hepatic mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.
抗精神病药物奥氮平的长期使用会诱发高甘油三酯血症，导致心血管疾病风险升高。然而，奥氮平短期使用对循环甘油三酯水平的影响及其潜在机制仍知之甚少。在此，研究了甘油三酯代谢调节剂载脂蛋白A5（apoA5）在奥氮平诱导的高甘油三酯血症中的作用。我们的多中心临床研究招募了36名接受短期（8周）奥氮平治疗的精神分裂症患者。此外，对雌性C57BL/6J小鼠给予奥氮平（3毫克/千克/天和6毫克/千克/天）治疗6周。我们证明，奥氮平的短期使用使患者和小鼠的血浆甘油三酯升高，血浆apoA5水平降低，这两个因素之间呈负相关。然而，在患者和小鼠中均未观察到肥胖。有趣的是，奥氮平使小鼠肝脏中的apoA5蛋白增加，而肝脏mRNA没有显著变化。一致地，研究表明奥氮平在人HepG2细胞和原代小鼠肝细胞中以剂量依赖性方式增加培养基甘油三酯水平并降低培养基apoA5水平。而奥氮平治疗增加了肝脏apoA5蛋白，但对肝脏mRNA没有影响。值得注意的是，荧光染色显示，在小鼠肝脏中，奥氮平增加了apoA5蛋白与肝细胞中积累的脂滴之间的共定位，而不是与肝细胞质膜的共定位。因此，我们的研究表明，奥氮平短期使用由于肝脏apoA5的分选和分泌缺陷而诱发高甘油三酯血症。
