Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and β
Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and β
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DOI：
10.1172/jci200418730
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发表时间：
2004-12-01
影响因子：
15.9
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Li, AC;Binder, CJ;Glass, CK
PPARalpha、beta/delta和gamma调节参与控制脂质代谢和炎症的基因，并在动脉粥样硬化病变的所有主要细胞类型中表达。体外研究表明，PPARs通过抑制促炎基因的表达和通过激活肝脏X受体-ABCA 1（LXR-ABCA 1）途径增强胆固醇流出来发挥抗动脉粥样硬化作用。为了研究这些活性在体内的潜在重要性，我们在雄性LDL受体缺陷（LDLR-/-）小鼠中对PPARalpha、β和γ激动剂对泡沫细胞形成和动脉粥样硬化的影响进行了系统分析。与PPARgamma激动剂一样，PPARalpha特异性激动剂强烈抑制动脉粥样硬化，而PPARbeta特异性激动剂不能抑制病变形成。与其对动脉粥样硬化的作用一致，PPARalpha和PPARgamma激动剂，但不是PPAPbeta激动剂，抑制腹腔中巨噬细胞泡沫细胞的形成。出乎意料的是，PPARalpha和PPARgamma激动剂通过不同的ABCA 1非依赖性途径抑制体内泡沫细胞形成。虽然抑制泡沫细胞形成的PPARalpha需要LXR，激活PPARgamma降低胆固醇酯化，诱导表达ABCG 1，并刺激HDL依赖性胆固醇流出的LXR-独立的方式。这些发现揭示了PPARs影响巨噬细胞胆固醇稳态的受体特异性机制。在未来，这些机制可能会被用来抑制动脉粥样硬化的发展。
PPARalpha, beta/delta, and gamma regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARalpha, beta, and gamma agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR-/-) mice. Like the PPARgamma agonist, a PPARalpha-specific agonist strongly inhibited atherosclerosis, whereas a PPARbeta-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARalpha and PPARgamma agonists, but not the PPAPbeta agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARalpha and PPARgamma agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARalpha required LXRs, activation of PPARgamma reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. in the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.