基于OCTN2调控机制的新型非典型抗精神病药物致脂代谢异常研究

Schizophrenia is a kind of severe mental disease, because its refractory and recidivity, long term drug treatment is inevitable. Although the second-generation of atypical antipsychotic drugs (AAPDs) have been used in the treatment of schizophrenia with no severe extrapyramidal syndrome, it will induce lipid metabolism disorder and increase the incidence rate of fatty liver, dyslipidemia and obesity. The mechanism of lipid metabolism disorder is complicated and unclear. We have found that AAPDs inhibited carnitine/organic cation transporter 2 (OCTN2) mediated uptake of L-carnitine (L-Car); clozapine, a typical drug of AAPDs, increased the renal excretion of L-Car, reduced the concentration of L-Car in plasma, liver and skeletal muscle, and down-regulated the expression of Octn2 and PPARs in mouse kidney. Considering the high expression of OCTN2 in kidney, and L-Car which plays crucial role in β-oxidation of fatty acid is a specific substrate of OCTN2, we hypothesized that AAPDs induced lipid metabolism disorder via inhibition of OCTN2 and down-regulation of OCTN2 via AMPK-PPAR, and subsequently reduction the renal re-absorption of L-Car, decreased the concentration of L-Car in liver and skeletal muscle, and resulted in the impairment of fatty acid β-oxidation. Supplement of L-Car or co-administration of agonist of AMPK/PPAR might improve the lipid metabolism disorder induced by AAPDs. Here we will apply human OCTN2 transfected cell model, primary cultured cells and mice (or clinical patients in some experiments) to study the effect of AAPDs on L-Car re-absorption mediated by OCTN2 underling mechanism, and to explore the strategy to attenuate the side effects based on the regulation of OCTN2. Our results will provide the helpful information to better application of AAPDs.

精神分裂症是一种重症精神疾病，因其难治愈性和复发性，需长期服用抗精神病药物。虽然AAPDs无严重锥体外系反应，但长期用药引起脂代谢异常致脂肪肝、肥胖的发生率显著升高。AAPDs致脂代谢异常的机制复杂。我们研究发现，AAPDs抑制OCTN2功能；其代表药物氯氮平增加小鼠L-Car肾排泄，降低血浆、肝脏、骨骼肌L-Car浓度，下调肾Octn2、PPARs表达。基于L-Car为OCTN2的特异性内源底物，且在脂肪酸β-氧化中发挥重要作用，我们推测AAPDs通过抑制OCTN2功能，并经AMPK/PPAR通路下调OCTN2表达，减少肾脏重吸收L-Car，降低肝脏、骨骼肌等L-Car水平，使脂肪酸氧化受阻，致脂代谢紊乱；补充L-Car或合用AMPK/PPAR激动剂可能改善AAPDs引起的脂代谢异常。本研究拟在不同水平阐明上述假说，并探索基于OCTN2调控机制的联合用药方案，为临床治疗方案设计提供依据。

精神分裂症是一种重症精神疾病，因其难治愈性和复发性，需长期服用抗精神病药物。虽然新型非典型抗精神病药物（atypical antipsychotic drugs，AAPDs）无严重锥体外系反应，但长期用药引起脂代谢异常致脂肪肝、肥胖的发生率显著升高。基于左旋肉碱（L-carnitine, L-Car）在脂肪酸β-氧化中的重要性，以及肉碱/有机阳离子转运体2（OCTN2）在介导L-Car细胞摄取、维持体内L-Car稳态中的作用，本研究首先应用稳定表达OCTN2的转基因细胞模型，考察多种非典型抗精神病药物对OCTN2的抑制作用，并以氯氮平和奥氮平为代表，从OCTN2和脂肪酸转运体功能和表达调控角度对两者致脂代谢异常机制进行了系统的研究。研究发现：氯氮平可通过抑制OCTN2功能、下调肾脏OCTN2表达，减少肾脏对L-Car的重吸收，降低体内L-Car浓度，致肝脏脂质堆积，补充L-Car可有效改善脂代谢异常；此外，氯氮平也可上调小鼠小肠和肝脏脂肪酸转运体表达，增加两者对脂肪酸的吸收，引起脂代谢异常。奥氮平虽然对OCTN2亦有很强的抑制，但并不影响小鼠肾脏L-Car排泄。进一步研究发现，奥氮平在小鼠体内的作用存在性别差异，对于雄性小鼠，奥氮平可抑制肝脏OCTN2功能和下调OCTN2表达，降低肝脏L-Car水平，减少脂肪酸β氧化，引起肝脏甘油三酯堆积；对于雌性小鼠，奥氮平并未下调OCTN2表达，而仅通过抑制肝脏OCTN2，降低肝脏L-Car水平，减弱肝脏脂肪酸β-氧化；外源补充L-Car可以明显改善奥氮平引起的肝脏脂肪变性。此外，奥氮平还可通过上调雌性小鼠肝脏中脂肪酸转运体FATP2和FABP1的表达，增加肝脏对脂肪酸的摄取，致甘油三酯堆积。本研究结果为改善氯氮平/奥氮平引起的脂代谢异常，改善精神病患者的生存质量、提高患者用药依从性，提供了实验依据。.此外，在本研究启发下，我们围绕OCTN2和脂肪酸转运体，阐明了妊娠期母体血浆L-Car降低的机制，且发现母体血浆L-Car降低并非妊娠期脂代谢异常的主要原因；同时还阐明了结肠OCTN2在炎症性肠病发生发展中的作用，以及炎症性肠病致脂代谢异常的可能机制。