Clozapine‐induced reduction of l‐carnitine reabsorption via inhibition/down‐regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice
Clozapine‐induced reduction of l‐carnitine reabsorption via inhibition/down‐regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice
复制标题
DOI：
10.1016/j.taap.2018.11.007
复制
发表时间：
2019-01
影响因子：
3.8
通讯作者：
Wei Wang;Mengru Bai;Ting Jiang;Cui Li;Ping Li;Hui Zhou;Zemin Wang;Li-ping Li-Li-ping-Li-1651122038;Huidi Jiang
中科院分区：
文献类型：
--
作者：
Wei Wang;Mengru Bai;Ting Jiang;Cui Li;Ping Li;Hui Zhou;Zemin Wang;Li-ping Li-Li-ping-Li-1651122038;Huidi Jiang
氯氮平是一种非典型的抗精神病药物，被广泛用于治疗精神分裂症;然而，氯氮平引起的代谢紊乱，如脂肪肝和体重增加，值得更多的关注。考虑到L-肉碱（L-Car）在脂肪酸氧化中的重要作用以及肉碱/有机阳离子转运蛋白（OCTN）2在L-Car的肾脏重吸收中的重要作用，我们旨在研究氯氮平诱导的肝脏脂质代谢紊乱是否与L-Car失调有关，通过抑制/下调肾脏OCTN 2。我们的结果显示，氯氮平抑制MDCK-hOCTN 2细胞摄取L-Car，IC 50值为1.78 μM。此外，氯氮平显著降低HK-2细胞、小鼠原代培养近端肾小管（mPCPT）细胞和HepG 2细胞中L-Car的摄取。以12.5、25和50 mg/kg剂量对小鼠进行急性（腹膜内注射）和连续21天口服给药，导致L-Car的肾脏排泄量是溶剂组的2-3倍，血浆和肝脏中的L-Car浓度显著降低。同时，肾脏中mOctn 2的mRNA和蛋白水平显著下调。此外，28天的口服给药氯氮平诱导小鼠肝脏中的甘油三酯（TG）和总胆固醇（TCHO）水平升高，而L-Car（40 mg/kg - 1 g/kg）以剂量依赖性方式减弱氯氮平诱导的肝脏TG和TCHO升高。这些结果表明，氯氮平诱导的L-Car重吸收减少/肾脏OCTN 2的下调有助于肝脏脂质代谢紊乱。补充L-Car可能是减轻氯氮平引起的脂质代谢异常的有效策略。
Clozapine, an atypical antipsychotic drug, is widely utilized for the treatment of schizophrenia; however, clozapine-induced metabolic disorders, such as fatty liver and weight gain, warrant increased attention. Considering the crucial role ofl-carnitine (L-Car) in fatty acid oxidation and carnitine/organic cation transporter (OCTN) 2 in renal reabsorption of L-Car, we aimed to study whether clozapine-induced liver lipid metabolic disorder is associated with L-Car dysregulationviainhibition/down-regulation of renal OCTN2. Our results reveal that clozapine inhibits L-Car uptake in MDCK-hOCTN2 cells with an IC50value of 1.78 μM. Additionally, clozapine significantly reduces the uptake of L-Car in HK-2 cells, mouse primary cultured proximal tubular (mPCPT) cells and HepG2 cells. Acute (intraperitoneal injection) and 21-day successive oral administration of clozapine at 12.5, 25, and 50 mg/kg to mice resulted in 2–3-fold greater renal excretion of L-Car than in the vehicle group, and the concentration of L-Car in plasma and liver was significantly decreased. Concomitantly, mRNA and protein levels of mOctn2 in the kidney were markedly down regulated. Additionally, 28-day oral administration of clozapine induced increased triglyceride (TG) and total cholesterol (TCHO) levels in mouse livers, while L-Car (40 mg/kg - 1 g/kg) attenuated clozapine-induced liver TG and TCHO increase in a dose-dependent manner. These results indicate that clozapine-induced reduction of L-Car reabsorptionviainhibition/down-regulation of renal OCTN2 contributes to liver lipid metabolic disorder. L-Car supplementation is probably an effective strategy to attenuate clozapine-induced abnormal lipid metabolism.