School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing, 400715, China.
NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing, 400715, China.
Acta Pharmacol Sin. 2024 Mar;45(3):502-516. doi: 10.1038/s41401-023-01180-w. Epub 2023 Oct 25.
Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 μM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.
奥氮平（OLZ）是一种广泛应用于治疗精神分裂症（SCZ）的抗精神病药物，其疗效较为理想。但其严重的代谢副作用往往会降低临床治疗的依从性和精神康复。由于其多靶点作用，OLZ 诱导的代谢紊乱的外周机制仍不清楚。内质网（ER）应激与细胞能量代谢和精神疾病的进展有关。在这项研究中，我们研究了 ER 应激在 OLZ 诱导的血脂异常发展中的作用。我们招募了 146 名接受 OLZ 单药治疗的 SCZ 患者，在基线时、治疗的第 4 周、第 12 周和第 24 周收集了血液样本和临床数据。这项病例对照研究表明，OLZ 治疗可显著升高血脂异常的 SCZ 患者血清内质网（ER）应激标志物 GRP78、ATF4 和 CHOP 的水平。在 HepG2 细胞中，OLZ（25、50 μM）剂量依赖性地增强了肝内从头脂肪生成，伴随着 SREBPs 的激活，同时引发了 ER 应激。牛磺熊脱氧胆酸（TUDCA）和 4-苯丁酸（4-PBA）抑制 ER 应激可减弱 OLZ 在体外和体内诱导的脂质失调。此外，我们证明了 ER 应激期间 PERK-CHOP 信号的激活是 OLZ 触发肝脏异常脂质代谢的主要原因，提示 PERK 可能是改善 OLZ 介导的脂质功能障碍的潜在靶点。总之，ER 应激抑制剂可能是治疗 SCZ 中 OLZ 诱导的血脂异常的一种潜在有效干预措施。
