Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice
Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice
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DOI：
10.1172/jci118687
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发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Branellec, D
中科院分区：
文献类型：
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作者：
Berthou, L;Duverger, N;Branellec, D
研究了贝特类药物对人载脂蛋白A-I基因表达的调节作用，在含有驱动肝脏载脂蛋白A-I表达的人基因组DNA片段的转基因小鼠中，（0.5%wt/wt）持续7天使血浆人载脂蛋白A-I水平增加至750%，HDL-胆固醇水平增加至200%，并向较大颗粒转移，人apo A-I血浆水平的增加具有时间和剂量依赖性，并且在最高剂量（0.5%wt/wt）的非诺贝特给药3天后已经明显。相反，非转基因小鼠中非诺贝特给药后血浆小鼠apo A-I浓度降低。非诺贝特治疗后血浆人载脂蛋白A-I水平的增加与肝脏人载脂蛋白A-I mRNA增加97%相关，而小鼠载脂蛋白A-I mRNA水平下降至51%。在非转基因小鼠中，观察到肝脏载脂蛋白A-I mRNA水平的类似下调，核连续实验表明，非诺贝特后人apo A-I基因表达的增加和小鼠apo A-I基因表达的减少发生在转录水平，由于贝特类药物的部分作用是通过核受体PPAR介导的，（过氧化物酶体增殖物激活受体），测量酰基CoA氧化酶（AGO）基因的表达作为PPAR激活的对照。在转基因和非转基因小鼠中，非诺贝特诱导ACO mRNA水平高达6倍，当用吉非罗齐（0.5% wt/wt）处理转基因小鼠时，血浆人载脂蛋白A-I和HDL-胆固醇水平分别比对照水平增加32%和73%。该化合物对人载脂蛋白A-I和HDL-胆固醇水平的影响较弱，与对ACO mRNA水平的影响不太明显（增加3倍）相关，表明人载脂蛋白A-I基因的诱导水平与所用贝特类药物的PPAR激活效力相关。用非诺贝酸（500 μ M）处理人原代肝细胞分别引起apo A-I分泌和mRNA水平增加83%和50%，支持贝特类对肝脏人apo A-I产生的直接作用导致观察到的血浆apo A-I和HDL-胆固醇增加。
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.