Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.

奥氮平可有效治疗精神分裂症和其他情绪障碍，但受副作用（如体重增加，血脂异常和肝损伤）的限制。在美国，肥胖症处于流行水平，是药物引起的肝损伤的重要危险因素。整体而言，精神病患者的肥胖发生率甚至高于美国人群。本研究的目的是检验肥胖加剧奥氮平诱导的肝损伤的假设，并研究萝卜硫烷的潜在保护作用。给8周大的雌性C57BL / 6小鼠喂食高脂或低脂对照饮食（HFD和LFD）。小鼠还通过渗透性微型泵接受了奥氮平（8 mg / kg / d）或溶媒给药4周。在HFD +奥氮平组中的一部分小鼠被给予了萝卜硫烷（一种典型的Nrf2诱导剂）（90 mg / kg / d）。仅奥氮平会增加体重，而食品消耗却不会相应增加。奥氮平还引起肝脂肪变性和损伤。奥氮平和HFD的组合会进一步引起葡萄糖和脂质代谢的失调。并发HFD和奥氮平对肝脏的损害要比高脂饮食或仅奥氮平对肝脏的损害更严重。萝卜硫烷减轻了奥氮平和HFD的许多代谢副作用。综上所述，这些数据表明，奥氮平会异常调节葡萄糖和脂质的代谢，并加剧因进食HFD而引起的肝脏变化。用萝卜硫烷激活内在的抗氧化剂防御途径可以部分预防奥氮平的这些作用，并且可能代表了预防肝损伤的有用策略。奥氮平还引起肝脂肪变性和损伤。奥氮平和HFD的组合会进一步引起葡萄糖和脂质代谢的失调。并发HFD和奥氮平对肝脏的损害要比高脂饮食或仅奥氮平对肝脏的损害更严重。萝卜硫烷减轻了奥氮平和HFD的许多代谢副作用。综上所述，这些数据表明，奥氮平会异常调节葡萄糖和脂质的代谢，并加剧因进食HFD而引起的肝脏变化。用萝卜硫烷激活内在的抗氧化剂防御途径可以部分预防奥氮平的这些作用，并且可能代表了预防肝损伤的有用策略。奥氮平还引起肝脂肪变性和损伤。奥氮平和HFD的组合会进一步引起葡萄糖和脂质代谢的失调。并发HFD和奥氮平对肝脏的损害要比高脂饮食或仅奥氮平对肝脏的损害更严重。萝卜硫烷减轻了奥氮平和HFD的许多代谢副作用。综上所述，这些数据表明，奥氮平会异常调节葡萄糖和脂质代谢，并加剧因进食HFD而引起的肝脏变化。用萝卜硫烷激活内在的抗氧化剂防御途径可以部分预防奥氮平的这些作用，并且可能代表了预防肝损伤的有用策略。并发HFD和奥氮平对肝脏的损害要比高脂饮食或仅奥氮平对肝脏的损害更严重。萝卜硫烷减轻了奥氮平和HFD的许多代谢副作用。综上所述，这些数据表明，奥氮平会异常调节葡萄糖和脂质的代谢，并加剧因进食HFD而引起的肝脏变化。用萝卜硫烷激活内在的抗氧化剂防御途径可以部分预防奥氮平的这些作用，并且可能代表了预防肝损伤的有用策略。并发HFD和奥氮平对肝脏的损害要比高脂饮食或仅奥氮平对肝脏的损害更严重。萝卜硫烷减轻了奥氮平和HFD的许多代谢副作用。综上所述，这些数据表明，奥氮平会异常调节葡萄糖和脂质代谢，并加剧因进食HFD而引起的肝脏变化。用萝卜硫烷激活内在的抗氧化剂防御途径可以部分预防奥氮平的这些作用，并且可能代表了防止肝损伤的有用策略。