LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling.
LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling.
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DOI：
10.7554/elife.08009
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发表时间：
2015-07-14
期刊：
影响因子：
7.7
通讯作者：
Tontonoz P
中科院分区：
文献类型：
--
作者：
Ito A;Hong C;Rong X;Zhu X;Tarling EJ;Hedde PN;Gratton E;Parks J;Tontonoz P
肝脏X受体（LXRs）是脂质稳态的转录调节因子，也具有有效的抗炎作用。其抗炎作用的分子基础尚未完全了解，但已提出涉及LXR与炎性基因启动子的间接拴系。在这里，我们证明了LXR抑制细胞和小鼠中炎症基因表达的能力主要来自于它们通过转录激活调节脂质代谢的能力，并且可以在没有SUMO化的情况下发生。此外，我们确定了假定的脂质转运蛋白Abca 1作为LXR抗炎作用的关键介质。LXR的激活通过Abca 1依赖性的膜脂质组织变化抑制TLR 2、4和9向其下游NF-κB和MAPK效应物的信号传导，从而破坏MyD 88和TRAF 6的募集。这些数据表明，一个共同的机制-直接转录激活-LXR在代谢和炎症的双重生物学功能的基础。DOI：http://dx.doi.org/10.7554/eLife.08009.001炎症是对感染或组织损伤的免疫反应的正常部分。然而，炎症增加与肥胖、糖尿病和动脉粥样硬化（动脉壁硬化）等疾病有关。这些疾病也与脂肪分子（如胆固醇）的产生或分解有关。转录因子是与DNA结合以控制基因表达的蛋白质。一种称为LXR的转录因子调节胆固醇的产生和分解，以应对体内胆固醇水平的变化。LXR也被证明可以抑制炎症反应，但以前的研究表明，LXR的这两种作用是相互独立的。Ito等人现在通过显示LXR通过改变胆固醇和其他脂肪分子的代谢来抑制炎症来挑战这些发现。这些实验使用了基因工程免疫细胞，称为巨噬细胞和小鼠，以表明激活LXR会导致胆固醇分子在细胞膜之间移动。这反过来又导致细胞表面蛋白质发出的信号发生变化，最终导致炎症反应减少。未来的工作将集中在更好地理解LXR对糖尿病和动脉粥样硬化等人类疾病模型中代谢和炎症的影响之间的联系。DOI：http://dx.doi.org/10.7554/eLife.08009.002网站
The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation. DOI: http://dx.doi.org/10.7554/eLife.08009.001 Inflammation is a normal part of the immune response to infection or tissue damage. However, increased inflammation has been linked to diseases such as obesity, diabetes and atherosclerosis (in which the walls of the arteries become hardened). These same diseases have also been linked to problems with the production or breakdown of fatty molecules, such as cholesterol. Transcription factors are proteins that bind to DNA to control gene expression. A transcription factor called LXR regulates the production and breakdown of cholesterol in response to changing levels of cholesterol in the body. LXR has also been shown to inhibit inflammatory responses, but previous studies suggested that these two actions of LXR are independent of each other. Ito et al. have now challenged these findings by showing that LXR inhibits inflammation via changes in the metabolism of cholesterol and other fatty molecules. The experiments used genetically engineered immune cells, called macrophages, and mice to show that activating LXR causes cholesterol molecules to move between the membranes in a cell. This in turn leads to changes in the signals sent by proteins found at the cell surface, and eventually to a reduction of inflammation responses. Future work will focus on better understanding the link between LXR's effects on metabolism and inflammation in models of human diseases such as diabetes and atherosclerosis. DOI: http://dx.doi.org/10.7554/eLife.08009.002