PPARä and AMPK as regulators of lipid metabolism and polarization of macrophages

低密度脂蛋白(LDL)的修饰在动脉粥样硬化的发展中起着至关重要的作用。在这些修饰中，分泌型磷脂酶A2(PLA2)对低密度脂蛋白(LDL)的降解作用最近引起了特别的关注，因为PLA2修饰的低密度脂蛋白(PLA2-LDL)可以诱导巨噬细胞泡沫细胞的形成。然而，这些表型变化的分子机制尚未解决。为了研究聚乳酸-低密度脂蛋白如何诱导泡沫细胞的形成，我们计划研究泡沫细胞形成的主要途径特征，如改变的细胞生存反应、脂质负荷和代谢以及炎症(失活)特征。表型改变的决定因素是过氧化物酶体增殖物激活受体(PPAR)和过氧化物酶体增殖物激活受体辅活化物1(PGC-1)。我们假设PLALDL解偶联线粒体以激活PGC-1，可能是通过钙和AMP-激酶途径，从而促进细胞存活。此外，我们假设聚乳酸-低密度脂蛋白与PGC-1一起激活PPARα和-δ，以解释炎性失活程序。此外，PPARδ和游离脂肪酸降解三磷酸腺苷结合盒转运体A1(ABCA1)支持脂质负荷。PPAR和PGC-1的协同作用可能会在巨噬细胞暴露于聚乳酸-低密度脂蛋白时引起脱敏泡沫细胞的形成。

Modifications of low density lipoproteins (LDL) are crucial to atherosclerosis development. Among these modifications LDL hydrolysis by secretory phospholipases A2 (PLA2) recently gained particular attention because PLA2-modified LDL (PLA-LDL) induces macrophage foam cell formation. However, molecular mechanisms of these phenotype changes are unresolved. To study how PLA-LDL induces foam cell formation we plan to investigate major pathways characteristic for foam cell formation such as an altered cell survival response, lipid loading and metabolism as well as the inflammatory (de)activation profile. Proposed determinants of the phenotype changes are the peroxisome proliferator-activated receptors (PPAR) and the peroxisome proliferator-activated receptor-coactivator 1 (PGC-1). We hypothesize that PLALDL uncouples mitochondria to activate PGC-1, presumably via a calcium and AMP-kinase pathway, thus promoting cell survival. Moreover, we assume activation of PPARα and -δ by PLA-LDL, in concert with PGC-1, to account for an inflammatory deactivation program. In addition, PPARδ and degradation of the ATP-binding cassette transporter A1 (ABCA1) by free fatty acids support lipid loading. The concerted action of PPARs and PGC-1 may provoke formation of a desensitized foam cell upon the exposure of macrophages to PLA-LDL.