奥氮平通过抑制载脂蛋白A5分泌导致非酒精性脂肪性肝病  

Olanzapine causes non-alcoholic fatty liver disease via inhibiting the secretion of apolipoprotein A5

作　　者：李蓉[1] 朱文强 黄飘飘 丁晨 汤雅新 连平安 黄贤圣[2] LI Rong;ZHUWenqiang;HUANG Piaopiao;DING Chen;TANG Yaxin;LIAN Ping’an;HUANG Xiansheng(Department of Stomatology,Second Xiangya Hospital,Central South University,Changsha 410011;Department of Cardiovascular Medicine,Second Xiangya Hospital,Central South University,Changsha 410011,China)

机构地区：[1]中南大学湘雅二医院口腔科,长沙410011 [2]中南大学湘雅二医院心血管内科,长沙410011

出　　处：《中南大学学报（医学版）》2022年第6期730-738,共9页Journal of Central South University ：Medical Science

基　　金：国家自然科学基金(81974281);湖南省自然科学基金(2020JJ2052);中国心血管健康联盟进阶基金(2019-CCAACCESS-2020JJ2052)。

摘　　要：目的:奥氮平是最常用第2代抗精神病药,若长期服用会显著增加发生非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的风险,但其发病机制不明。肝内脂肪过度沉积是NAFLD的病理基础,且与肝内TG代谢障碍密切相关。载脂蛋白A5(apolipoprotein A5,ApoA5)是体内TG代谢的关键调节因子,促进肝细胞内TG蓄积,参与NAFLD发病。然而,奥氮平是否通过ApoA5诱发NAFLD尚无报道。本研究探讨ApoA5是否参与奥氮平相关NAFLD的发病。方法:从动物实验、细胞实验及ApoA5基因敲低实验3个层次上进行探讨。将6周龄雄性C57BL/6J小鼠随机分为对照组、低剂量组、高剂量组,分别给予10%DMSO、3 mg/(kg·d)奥氮平、6 mg/(kg·d)奥氮平。干预8周后,测定各组小鼠的血脂4项、肝转氨酶2项和ApoA5水平。HepG2细胞分为对照组、低剂量组、中剂量组、高剂量组,分别给予0.1%DMSO、25μmol/L奥氮平、50μmol/L奥氮平、100μmol/L奥氮平干预24 h。对100μmol/L奥氮平预处理的HepG2细胞分别转染ApoA5 siRNA或scrambled siRNA(阴性对照)。采用油红O染色观察肝组织和肝细胞中的脂滴;HE染色观察肝组织脂质沉积情况;实时PCR检测ApoA5 mRNA表达水平;蛋白质印迹法检测ApoA5蛋白质表达水平。结果:3或6 mg/(kg·d)的奥氮平干预后,各组小鼠体重差异无统计学意义(P>0.05),血浆TG、ALT和AST水平呈剂量依赖性升高,血浆ApoA5水平呈剂量依赖性降低(均P<0.05);但各组小鼠血浆胆固醇(HDL-C、LDL-C、TC)水平差异均无统计学意义(均P>0.05)。肝组织中ApoA5蛋白质水平呈剂量依赖性升高(均P<0.05),但各组ApoA5 mRNA表达差异无统计学意义(P>0.05)。对照组小鼠肝组织结构完整,肝细胞形态规则,细胞内仅见少量散在脂滴;给予3或6 mg/(kg·d)奥氮平的小鼠肝细胞内可见大量脂肪沉积,细胞呈气球样变,充盈着大量的脂滴空泡,细胞核位于细胞边缘,红色脂滴数量明显增多,且高剂量组更明显�Objective:Long-term treatment of olanzapine,the most widely-prescribed secondgeneration antipsychotic,remarkably increases the risk of non-alcoholic fatty liver disease(NAFLD),whereas the mechanism for olanzapine-induced NAFLD remains unknown.Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD,which results from the disturbance of TG metabolism in the liver.Apolipoprotein A5(Apo A5)is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes,thereby resulting in the development of NAFLD.However,there are no data indicating the role of apo A5 in olanzapine-induced NAFLD.Therefore,this study aims to investigate the role of apo A5 in olanzapine-induced NAFLD.Methods:This study was carried out via animal studies,cell experiment,and Apo A5 gene knockdown experiment.Six-week-old male C57BL/6J mice were randomized into a control group,a low-dose group,and a high-dose group,which were treated by 10%DMSO,3 mg/(kg·d)olanzapine,and 6 mg/(kg·d)olanzapine,respectively for 8 weeks.The lipid levels in plasma,liver function indexes,and expression levels of Apo A5 were detected.Hep G2 cells were treated with 0.1%DMSO(control group),25μmol/L olanzapine(low-dose group),50μmol/L olanzapine(medium-dose group),and 100μmol/L olanzapine(high-dose group)for 24 h.Hep G2 cells pretreated with 100μmol/L olanzapine were transfected with si RNA and scrambled si RNA(negative control),respectively.We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining.The m RNA and protein levels of Apo A5 were determined by real-time PCR and Western blotting,respectively.Results:After intervention with 3 and 6 mg/(kg·d)olanzapine for 8 weeks,there was no significant difference in body weight among the 3 groups(P>0.05).Olanzapine dosedependently increased the plasma TG,ALT and AST levels,and reduced plasma Apo A5levels(all P<0.05),whereas there was no significant difference in plasma cholesterol(HDL-C,LDL

关 键 词：奥氮平 载脂蛋白A5 非酒精性脂肪性肝病 三酰甘油 

分 类 号：R965[医药卫生—药理学]