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。

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.