成纤维细胞生长因子21表达抑制对ApoE基因敲除小鼠糖脂代谢的影响  

Effects of FGF-21 gene knockdown on glucose and lipid metabolism in ApoE-/- mice

作　　者：罗妤[1] 邓广江[2] 杨刚毅[2] 李伶[1] 张莉莉[2] 王波[2] Gunther Boden 李钶[2] 李生兵[2] 

机构地区：[1]重庆医科大学检验系,临床生化教研室和教育部实验诊断重点实验室,400010 [2]重庆医科大学附属第二医院内分泌科 [3]美国Temple大学医学院附属医院一般临床研究中心

出　　处：《中华内分泌代谢杂志》2011年第12期1004-1008,共5页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金项目（30771037,30871199,30971388,81070640）;美国NIH基金（5R01HL0732555567-04 to Boden）;诺和诺德公司科研基金

摘　　要：目的 探讨抑制成纤维细胞生长因子21（FGF-21）基因表达抑制对ApoE基因敲除（ ApoE-/-）小鼠糖脂代谢的影响.方法 采用C57 BL/6J为对照组（n=10）,ApoE-/-小鼠随机分为普食组（NF组,n=10）；普食＋pAd-shFGF-21组（NFG组,n=9）；高脂饲料组（HF组,n=10）；高脂＋pAd-shFGF-21组（ HFG,n=10）；高脂＋空载体组（GFP,n=6）,均喂养16周,NFG和HFG组于15周末予尾静脉注射pAd-shFGF-21.采用3-[3H]葡萄糖为示踪剂的扩展高胰岛素钳夹技术评价各组小鼠胰岛素敏感性和糖脂代谢变化.结果 NFG和HFG组血浆FGF-21水平较相应对照组降低20％～27％（均P＜0.05）.基础状态下,NFG和HFG组空腹血糖、血浆胰岛素、游离脂肪酸、总胆固醇、甘油三酯、低密度脂蛋白胆固醇（LDL-C）水平均显著高于NF和HF组（P＜0.05或P＜0.01）,而高密度脂蛋白胆固醇（HDL-C）则显著低于NF和HF组（P＜0.01）.钳夹稳态时,NFG和HFG组游离脂肪酸虽被抑制,但分别明显高于NF和HF组（P＜0.01或P＜0.05）.在相同胰岛素浓度输注下,NFG和HFG组葡萄糖输注率（GIR）分别明显低于NF和HF组（P＜0.01）.钳夹结束时,NFG和HFG组的葡萄糖清除率（GRd）分别明显低于NF和HF组（均P＜0.01）,而肝糖输出率（HGP）则分别明显高于NF和HF组,仅被抑制49％和20％（均P＜0.01）.结论 FGF-21表达抑制和血浆FGF-21水平降低加重了机体糖脂代谢紊乱和胰岛素抵抗.Objective To investigate the in vivo effects of down-regulating the FGF-21 gene expression by shRNA on glucose and lipids metabolism in high fat diet （HFD） fed ApoE-/- mice.Methoeds Male ApoE-/- mice were randomly divided into chow diet （CF）fed group （ NF,n =10）,CF fed ＋ pAd-shFGF-21 group （ NFG,n =9）,and HFD fed group （ HF,n =10）,HFD fed ＋ Adv-null vector （ pAd-GFP ） group （ GFP,n =6） and HFD fed ＋ pAd-shFGF-21 group （ HFG,n =10）.Mice were fed for 16 weeks.C57BL/6J mice were set as control group （ NC group,n=10）.NFG,HFG,and GFP groups were injected with pAd-shFGF-21or pAd-GFP by tail vein at the end of 15 weeks.The insulin sensitivity and glucoselipid metabolism were assessed by the hyperinsulinemic- euglycemic clamp technique using 3-[ 3 H] glucose as a tracer at the end of 16 week.Results The plasma FGF-21 levels in NFG and HFG groups were significantly degraded than those in NF and HF groups（20%-27%,P〈0.05）,respectively.In the basal state,the fasting blood glucose,fasting plasma insulin,free fatty-acids,triglycerides,total cholesterol,and LDL-C were significantly higher,while the HDL-C was lower in NFG and HFG groups compared with those in NF and HF groups,respectively （P〈0.05 or P〈0.01 ）.During the steady-state of clamp,FFA was suppressed in all groups,but it was still higher in NFG and HFG groups than NF and HF groups （ P〈0.05or P〈0.01 ）.The glucose infusion rate （GIR）and glucose disappearance rate （GRd）in NFG and HFG groups were significantly decreased compared with NF and HF groups （all P〈0.01 ）.In addition,insulin＇s ability to suppress hepatic glucose production （HGP） during clamps was significantly decreased in HFG and NFG group compared with HF and NF groups （49% and 20%,respectively; all P〈0.01 ）.Conclusion FGF-21 knockdown and low FGF-21 level facilitate the development of metabolic disorder and insulin resistance.

关 键 词：成纤维细胞生长因子21 RNA干扰 胰岛素抵抗 糖脂代谢 

分 类 号：R587.1[医药卫生—内分泌]