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

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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.