University Lille Nord de France, Lille, France.
Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1573-9. doi: 10.1161/ATVBAHA.110.220525. Epub 2011 Apr 7.
Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice.
Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPARα-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/- apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/-, and PPARα-/- apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner.
These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
过氧化物酶体增殖物激活受体-α（PPARα）是一种配体激活的转录因子，可控制脂质代谢和炎症。PPARα 被贝特类药物激活，贝特类药物是用于治疗血脂异常的降脂药物。先前评估 PPARα 激动剂对小鼠动脉粥样硬化影响的研究结果存在矛盾，其在其中的影响尚未得到评估。人类载脂蛋白 E2 敲入（apoE2-KI）小鼠是一种混合性血脂异常、动脉粥样硬化和非酒精性脂肪性肝炎（NASH）的模型。本研究旨在使用同型和异型 PPARα 缺陷小鼠分析定量变异的 PPARα 基因水平及其对合成 PPARα 激动剂非诺贝特对 apoE2-KI 小鼠 NASH 和动脉粥样硬化的影响。
在 apoE2-KI 背景下生成了野生型（+/+）、杂合型（+/−）和纯合型（−/−）PPARα 缺陷小鼠，并使其接受添加或不添加非诺贝特的西方饮食。与 PPARα+/+ 和 PPARα+/− apoE2-KI 小鼠相比，西方饮食喂养的 PPARα-/-apoE2-KI 小鼠的肝脏脂肪变性和炎症加重，表明 PPARα 在肝脏保护中起作用。此外，PPARα 表达是 fenofibrate 诱导对 NASH 保护所必需的。有趣的是，fenofibrate 治疗在 PPARα+/+ 和 PPARα+/− apoE2-KI 小鼠中对肝脂质代谢产生相似的反应，而对于最大的抗炎反应，则需要 PPARα 基因的两个等位基因。令人惊讶的是，PPARα+/+、PPARα+/−和 PPARα-/-apoE2-KI 小鼠之间的动脉粥样硬化发展没有显著差异。然而，PPARα 基因水平以剂量依赖的方式决定了 fenofibrate 对动脉粥样硬化的抗动脉粥样硬化和血管抗炎反应。
这些结果表明，PPARα 在调节肝脏代谢、炎症和动脉粥样硬化形成方面具有必要但定量不同的作用。
