Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice

被引:220
作者
Berthou, L
Duverger, N
Emmanuel, F
Langouet, S
Auwerx, J
Guillouzo, A
Fruchart, JC
Rubin, E
Denefle, P
Staels, B
Branellec, D
机构
[1] INST PASTEUR,INSERM U325,DEPT ATHEROSCLEROSE,F-59019 LILLE,FRANCE
[2] RHONE POULENC RORER GENCELL,CRVA,DEPT BIOTECHNOL,F-94403 VITRY SUR SEINE,FRANCE
[3] HOP PONTCHAILLOU,U49 INSERM,F-35033 RENNES,FRANCE
[4] UNIV CALIF BERKELEY,LAWRENCE BERKELEY LAB,BERKELEY,CA 94720
关键词
gene regulation; atherosclerosis; HDL-cholesterol; hypolipidemic drugs; peroxisome proliferation;
D O I
10.1172/JCI118687
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The regulation of liver apolipoprotein (ape) A-I gene expression by fibrates was studied in human apo A-I transgenic mice containing a human genomic DNA fragment driving apo A-I expression in liver, Treatment with fenofibrate (0.5% wt/wt) for 7 d increased plasma human apo A-I levels up to 750% and HDL-cholesterol levels up to 200% with a shift to larger particles, The increase in human apo A-I plasma levels was time and dose dependent and was already evident after 3 d at the highest dose (0.5% wt/wt) of fenofibrate, In contrast, plasma mouse apo A-I concentration was decreased after fenofibrate in nontransgenic mice. The increase in plasma human apo A-I levels after fenofibrate treatment was associated with a 97% increase in hepatic human apo A-I mRNA, whereas mouse apo A-I mRNA levels decreased to 51%, In nontransgenic mice, a similar down-regulation of hepatic apo A-I mRNA levels was observed, Nuclear run-on experiments demonstrated that the increase in human apo A-I and the decrease in mouse apo A-I gene expression after fenofibrate occurred at the transcriptional level, Since part of the effects of fibrates are mediated through the nuclear receptor PPAR (peroxisome proliferator-activated receptor), the expression of the acyl CoA oxidase (AGO) gene was measured as a control of PPAR activation, Both in transgenic and nontransgenic mice, fenofibrate induced ACO mRNA levels up to sixfold, When transgenic mice were treated with gemfibrozil (0.5% wt/wt) plasma human apo A-I and HDL-cholesterol levels increased 32 and 73%, respectively, above control levels. The weaker effect of this compound on human apo A-I and HDL-cholesterol levels correlated with a less pronounced impact on ACO mRNA levels (a threefold increase) suggesting that the level of induction of human apo A-I gene is related to the PPAR activating potency of the fibrate used. Treatment of human primary hepatocytes with fenofibric acid (500 mu M) Provoked an 83 and 50% increase in apo A-I secretion and mRNA levels, respectively, supporting that a direct action of fibrates on liver human apo A-I production leads to the observed increase in plasma apo A-I and HDL-cholesterol.
引用
收藏
页码:2408 / 2416
页数:9
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