Identification of macrophage liver X receptors as inhibitors of atherosclerosis
Identification of macrophage liver X receptors as inhibitors of atherosclerosis
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DOI：
10.1073/pnas.182199799
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发表时间：
2002-09-03
影响因子：
11.1
通讯作者：
Schulman, IG
中科院分区：
文献类型：
--
作者：
Tangirala, RK;Bischoff, ED;Schulman, IG
最近的研究已经确定肝脏X受体（LXR α和LXR β）作为胆固醇代谢和运输的重要调节剂。LXR控制对一系列生物学功能至关重要的基因的转录，所述生物学功能包括调节高密度脂蛋白胆固醇代谢、肝胆固醇代谢和肠固醇吸收。虽然LXR活性已被认为是生理脂质代谢和运输的关键，但将LXR信号通路与心血管疾病发病机制联系起来的直接证据尚未建立。在这项研究中，骨髓移植被用来选择性地消除巨噬细胞LXR表达的背景下，小鼠模型的动脉粥样硬化。我们的研究结果表明，LXR是动脉粥样硬化形成的内源性抑制剂。此外，骨髓来源的细胞中LXR活性的消除模拟了丹吉尔病（一种人类高密度脂蛋白缺乏症）的许多方面，包括胆固醇转运蛋白表达的异常调节、巨噬细胞中的脂质积聚、脾肿大和动脉粥样硬化增加。这些结果将LXR确定为心血管疾病干预的靶点。
Recent studies have identified the liver X receptors (LXRalpha and LXRbeta) as important regulators of cholesterol metabolism and transport. LXRs control transcription of genes critical to a range of biological functions including regulation of high density lipoprotein cholesterol metabolism, hepatic cholesterol catabolism, and intestinal sterol absorption. Although LXR activity has been proposed to be critical for physiologic lipid metabolism and transport, direct evidence linking LXR signaling pathways to the pathogenesis of cardiovascular disease has yet to be established. In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. Our results demonstrate that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identify LXRs as targets for intervention in cardiovascular disease.