Department of Pharmacology, Esperion Therapeutics Inc., Plymouth, MI 48170, USA.
Mol Cell Biochem. 2010 Dec;345(1-2):197-206. doi: 10.1007/s11010-010-0573-8. Epub 2010 Aug 27.
Cholesterol ester transfer protein (CETP) and apolipoprotein (apo) E are important in peroxisome proliferation activated receptor-α (PPAR-α)-mediated regulation of lipoprotein metabolism. Therefore, popularly used apolipoprotein E knockout mice are not suitable to evaluate PPAR-α agonists. In this study, we aimed to: a) evaluate hamster as a model for insulin resistance, hyperlipidemia and atherosclerosis; and b) investigate the effect of a PPAR-α activator, fenofibrate, in this model. A high fat high cholesterol (HFHC) diet increased serum cholesterol and triglycerides, but inclusion of fenofibrate in the diet decreased cholesterol and proatherogenic lipoproteins, VLDL and LDL, in a time-dependent manner. Concomitantly, serum levels of triglycerides also decreased. These reductions were attributed, in part, to the down-regulation of lipogenic genes and upregulation of lipoprotein lipase. The HFHC diet caused body weight gain and mild insulin resistance, both of which were prevented following the treatments with fenofibrate. Insulin resistance was further investigated in high fructose-fed hamsters. Fenofibrate prevented both hyperinsulinemia and hypertriglyceridemia. The insulin sensitizing activity of fenofibrate appeared to occur via reductions in protein tyrosine phophatase-1B. To determine whether lowering of lipids by fenofibrate treatment contributed to the reduced risks of developing atherosclerosis in hyperlipidemic hamsters, we measured lipid deposition in the aorta. Our results showed that fenofibrate treatment reduced aortic lipid deposition by 70%. These findings suggest that hamster may be an adequate animal model to evaluate the efficacy of lipid lowering, insulin sensitizing and antiatherosclerotic agents. We also show that fenofibrate is an effective antiatherosclerotic agent in hyperlipidemic hamster model.
胆固醇酯转移蛋白（CETP）和载脂蛋白（apo）E 在过氧化物酶体增殖物激活受体-α（PPAR-α）介导的脂蛋白代谢调节中非常重要。因此，常用的载脂蛋白 E 敲除小鼠不适合评估 PPAR-α 激动剂。在本研究中，我们旨在：a）评估仓鼠作为胰岛素抵抗、高脂血症和动脉粥样硬化的模型；b）研究 PPAR-α 激活剂非诺贝特在该模型中的作用。高脂肪高胆固醇（HFHC）饮食增加了血清胆固醇和甘油三酯，但饮食中添加非诺贝特可使胆固醇和致动脉粥样硬化脂蛋白（VLDL 和 LDL）呈时间依赖性降低。同时，血清甘油三酯水平也降低。这些减少部分归因于脂肪生成基因的下调和脂蛋白脂肪酶的上调。HFHC 饮食导致体重增加和轻度胰岛素抵抗，非诺贝特治疗可预防这些情况。在高果糖喂养的仓鼠中进一步研究了胰岛素抵抗。非诺贝特可预防高胰岛素血症和高甘油三酯血症。非诺贝特的胰岛素增敏作用似乎是通过降低蛋白酪氨酸磷酸酶-1B 实现的。为了确定非诺贝特治疗降低血脂是否有助于降低高脂血症仓鼠发生动脉粥样硬化的风险，我们测量了主动脉中的脂质沉积。我们的结果表明，非诺贝特治疗可使主动脉脂质沉积减少 70%。这些发现表明，仓鼠可能是评估降脂、胰岛素增敏和抗动脉粥样硬化药物疗效的合适动物模型。我们还表明，非诺贝特是高脂血症仓鼠模型中一种有效的抗动脉粥样硬化药物。
