金黄地鼠高脂血症模型甘油三酯代谢紊乱的生物标志物的研究  

Triglyceride disorder biomakers in hyperlipidemic hamsters

作　　者：初欣欣 杨润梅[1] 于莹[1,2] 康卓颖 冀敏[1] 高南南[1] 

机构地区：[1]中国医学科学院北京协和医学院药用植物研究所药理毒理研究中心,北京100193 [2]哈尔滨商业大学生命科学与环境科学研究中心,黑龙江哈尔滨150076

出　　处：《中国药理学通报》2014年第7期1012-1017,共6页Chinese Pharmacological Bulletin

基　　金：国家科技部"重大新药创制"科技重大专项资助项目(No2012ZX09301002-001-026)

摘　　要：目的建立金黄地鼠高脂血症模型,并研究甘油三酯代谢紊乱的分子机制。方法金黄地鼠随机分为正常组和模型组,正常组饲常规饲料,模型组饲高脂饲料,连续诱导4周。于第2、4周检测血清TG、TC、LDL-C、FFA水平和LPL活性,应用荧光实时定量PCR技术探讨甘油三酯代谢紊乱的分子机制。同时观察阳性药非诺贝特对金黄地鼠高脂血症模型血脂的影响。结果金黄地鼠造模2周时,血清TG、TC、LDL-C、FFA与对照组比较分别升高2.57、1.93、2.49和1.25倍;造模4周时分别升高3.93、1.90、2.27和2.29倍。阳性药对TG和FFA升高有明显的抑制作用。机制研究表明,金黄地鼠造模后,肝脏AMPK、PPARα、CPT-1 mRNA表达降低,SREBP-1c、ACC、SCD-1、AGPAT2、DGAT2 mRNA表达上调。ApoB表达有上调趋势,MTTP和LPL表达有下调趋势,血浆LPL活性明显降低。这些酶、蛋白、受体的表达变化是金黄地鼠甘油三酯代谢紊乱的主要原因。结论金黄地鼠经高脂饲料诱导4周后形成了具有高甘油三酯血症特征的高脂血症模型,AMPK、SREBP-1c、ACC、SCD1、DGAT2、AGPAT2、PPARα、CPT-1、LPL既是金黄地鼠甘油三酯代谢紊乱的生物标志物,也是降甘油三酯药物的作用靶标。Aim To establish hyperlipidemic model and study the molecular mechanism of triglyceride （TG）disorder in hamsters.Methods The male ham-sters were randomly divided to control group fed with standard diet and model group fed with high-fat diet, both of the groups had been fed with diet for 4 weeks. The levels of serum TG,TC,LDL-C,FFA were detec-ted at the end of 2nd and 4th week.The hepatic TG, TC,LPL activity were detected by enzymatic method at the end of 4th week.The molecular mechanism was tested by real-time PCR.Meanwhile the effect of posi-tive drug fenofibrate on the model of hyperlipidemia in hamsters was investigated.Results Compared with the control,the serum levels of TG,TC,LDL-C,FFA in the model group increased 2.57,1.93,2.49,1.25 times at the end of2nd week,and 3.93,1.90,2.27, 2.29 times at the end of 4th week,respectively.The positive drug significantly decreased the concentrations of serum TG and FFA. The mechanism research＆amp;nbsp;showed that the hepatic AMPK,PPARα,CPT-1 mRNA decreased in hamsters fed with high-fat diet,and the SREBP-1 c,ACC,SCD-1 ,AGPAT2,DGAT2 mRNA ex-pressions increased.The hepatic ApoB mRNA expres-sion was up-regulated while the MTTP and LPL mRNA expressions were down-regulated slightly.LPL activity significantly decreased in model hamsters compared with the control.The alternations of these enzymes and receptors were the critical factors for TG disorder. Conclusion The hamsters fed with high-fat diet for 4 weeks can form a good hyperlipemic model with HTG feature.AMPK,SREBP-1 c,ACC,SCD-1 ,DGAT2,AG-PAT2,PPARα,CPT-1 and LPL are not only the main mechanisms of TG disorder,but also the biomarkers of hypotriglyceridemic drugs.

关 键 词：金黄地鼠 高脂血症 甘油三酯代谢紊乱 AMPK SREBP-1C ACC SCD-1 AGPAT2 DGAT2 PPARα CPT-1 LPL 

分 类 号：R332[医药卫生—人体生理学] R344.3[医药卫生—基础医学]