Fenofibrate Increases Very Low Density Lipoprotein Triglyceride Production Despite Reducing Plasma Triglyceride Levels in APOE*3-Leiden.CETP Mice
Fenofibrate Increases Very Low Density Lipoprotein Triglyceride Production Despite Reducing Plasma Triglyceride Levels in APOE*3-Leiden.CETP Mice
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DOI：
10.1074/jbc.m110.123992
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发表时间：
2010-08-13
影响因子：
4.8
通讯作者：
Rensen, Patrick C. N.
中科院分区：
文献类型：
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作者：
Bijland, Silvia;Pieterman, Elsbet J.;Rensen, Patrick C. N.
过氧化物酶体增殖物激活受体α（PPAR α）激活剂非诺贝特可有效降低血浆甘油三酯（TG），这通常归因于极低密度脂蛋白（VLDL）-TG清除率提高和VLDL-TG产生减少。然而，由于关于非诺贝特对VLDL产生的影响的数据存在争议，我们旨在通过使用APOE*3-Leiden.CETP小鼠（一种独特的类人脂蛋白代谢小鼠模型）研究VLDL-TG产生和清除来（更）详细地研究TG降低作用的机制。雄性小鼠喂食西式饮食4周，然后喂食不含或含非诺贝特（30 mg/kg体重/天）的相同饮食4周。非诺贝特显著降低VLDL降低引起的血浆胆固醇（-38%）和TG（-60%）。根据甘油三[H-3]油酸酯标记的VLDL样乳剂颗粒的血浆半衰期缩短（-68%）判断，非诺贝特显著加速VLDL-TG清除。这与肝素后脂蛋白脂肪酶（LPL）活性增加（+110%）和骨骼肌、白色脂肪组织和肝脏对VLDL衍生脂肪酸的摄取增加相关。同时，非诺贝特显著增加VLDL-TG生成率（+73%），但不增加VLDL-载脂蛋白B（apoB）生成率。使用[H-3]棕榈酸的动力学研究表明，非诺贝特通过同等增加再酯化血浆脂肪酸和肝脏TG掺入VLDL，增加了VLDL-TG的产生，这得到了肝脏基因表达谱数据的支持。我们的结论是，非诺贝特降低血浆TG通过增强脂蛋白介导的VLDL-TG清除，这导致在VLDL-TG生产的肝脏代偿性增加。
The peroxisome proliferator-activated receptor alpha (PPAR alpha) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%) and TG (-60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of glycerol tri[H-3]oleate-labeled VLDL-like emulsion particles (-68%). This was associated with an increased post-heparin lipoprotein lipase (LPL) activity (+110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [H-3] palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.