Töröcsik Dániel, Szanto Attila, Nagy László
Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine, Hungary.
Mol Aspects Med. 2009 Jun;30(3):134-52. doi: 10.1016/j.mam.2009.02.002. Epub 2009 Feb 25.
Sterols and fatty acids are common intermediary metabolites in all cells of the body. Oxidative modifications of these molecules can occur and result in the production of oxysterols and oxidized fatty acids. Significantly, these modified molecules not only participate in basic metabolic processes but they are also involved in signaling pathways. These two groups of molecules are known to regulate the activity of a special group of ligand-activated transcription factors, known as nuclear receptors. Oxysterols activate liver X receptor (LXR), while oxidized fatty acids regulate peroxisome proliferator-activated receptors (PPARs). These nuclear hormone receptors control the expression of their target genes upon ligand binding and via this effect many physiological as well as pathological processes. The role of the receptors and natural or synthetic activators have been studied extensively in the initiation, development and progression of atherosclerosis. Both the receptors themselves and their activators have been shown to exert anti-atherogenic effects. In this review we provide an overview of oxysterol-driven gene expression regulation. We introduce nuclear receptors, in particular LXR, how they become activated by oxysterols, how they work, what consequences of receptor activation on transcription regulation has and how these processes coordinate cholesterol metabolism and transport in macrophages. We place LXR into a network of transcription factors, enzymes and ligands. We also summarize data supporting the notion that LXR is also involved in the regulation of inflammatory processes. Finally, the in vivo consequences of LXR activation or deletion are discussed.
甾醇和脂肪酸是人体所有细胞中常见的中间代谢产物。这些分子可发生氧化修饰，产生氧化甾醇和氧化脂肪酸。值得注意的是，这些修饰分子不仅参与基本代谢过程，还参与信号通路。已知这两类分子可调节一类特殊的配体激活转录因子（即核受体）的活性。氧化甾醇激活肝X受体（LXR），而氧化脂肪酸调节过氧化物酶体增殖物激活受体（PPARs）。这些核激素受体在配体结合后控制其靶基因的表达，并通过这种作用影响许多生理和病理过程。在动脉粥样硬化的发生、发展和进展过程中，对这些受体及其天然或合成激活剂的作用进行了广泛研究。已证明受体本身及其激活剂均具有抗动脉粥样硬化作用。在本综述中，我们概述了氧化甾醇驱动的基因表达调控。我们介绍核受体，特别是LXR，它们如何被氧化甾醇激活、如何发挥作用、受体激活对转录调控有何影响，以及这些过程如何协调巨噬细胞中的胆固醇代谢和转运。我们将LXR置于转录因子、酶和配体的网络中。我们还总结了支持LXR也参与炎症过程调控这一观点的数据。最后，讨论了LXR激活或缺失在体内的后果。
