Prieur Xavier, Roszer Tamás, Ricote Mercedes
Institute of Metabolic Science, Metabolic Research Laboratories and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Biochim Biophys Acta. 2010 Mar;1801(3):327-37. doi: 10.1016/j.bbalip.2009.09.017. Epub 2009 Sep 29.
Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFkappaB) and the key roles played by the PPAR and LXR nuclear receptors-lipid sensors that link lipid metabolism and inflammation.
非脂肪组织内脂质代谢产物的积累可通过促进巨噬细胞浸润和激活来诱导慢性炎症。长期以来，人们已知氧化型和糖基化脂蛋白、游离脂肪酸、游离胆固醇、三酰甘油、二酰甘油和神经酰胺通过其促炎和促凋亡特性诱导细胞功能障碍。新出现的证据表明，脂质代谢产物激活巨噬细胞并通过脂质信号进一步调节，是动脉粥样硬化、肥胖相关胰岛素抵抗以及与代谢综合征相关的炎症性疾病（如肝脂肪变性和慢性肾脏病）中脂毒性的常见致病机制。在本综述中，我们讨论了支持脂质在不同代谢疾病中调节巨噬细胞表型作用的最新发现。我们描述了脂质衍生物通过调节巨噬细胞功能促进动脉壁斑块不稳定、损害胰岛素反应性并导致炎症性肝病、肌肉病和肾病的共同机制。我们讨论了促炎途径（JNK、NFκB）的脂质激活分子机制以及连接脂质代谢和炎症的PPAR和LXR核受体——脂质传感器所起的关键作用。
