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

PPARα 和 AMPK 作为脂质代谢和巨噬细胞极化的调节剂

基本信息

批准号：
68625409
负责人：
Professor Dr. Bernhard Brüne
金额：
--
依托单位：
Institut für Biochemie I: Pathobiochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/68625409?language=en
关键词：
PPAR AMPK regulators lipid metabolism

项目摘要

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.

低密度脂蛋白（LDL）的修饰对动脉粥样硬化的发展至关重要。在这些修饰中，分泌型磷脂酶A2（PLA 2）对LDL的水解最近获得了特别的关注，因为PLA 2修饰的LDL（PLA-LDL）诱导巨噬细胞泡沫细胞形成。然而，这些表型变化的分子机制尚未解决。为了研究PLA-LDL如何诱导泡沫细胞形成，我们计划研究泡沫细胞形成的主要途径特征，如改变细胞存活反应，脂质负荷和代谢以及炎症（去）活化特征。提出的表型变化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-共激活因子1（PGC-1）。我们推测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PLA-LDL与PGC-1协同激活PPARα和-δ，以解释炎症失活程序。此外，过氧化物酶体增殖物激活受体δ和ATP结合盒转运蛋白A1（ABCA 1）被游离脂肪酸降解支持脂质负荷。PPARs和PGC-1的协同作用可能引起巨噬细胞暴露于PLA-LDL后形成脱敏泡沫细胞。