Laffitte B A, Repa J J, Joseph S B, Wilpitz D C, Kast H R, Mangelsdorf D J, Tontonoz P
Howard Hughes Medical Institute, Department of Pathology, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):507-12. doi: 10.1073/pnas.98.2.507. Epub 2001 Jan 9.
Apolipoprotein E (apoE) secreted by macrophages in the artery wall exerts an important protective effect against the development of atherosclerosis, presumably through its ability to promote lipid efflux. Previous studies have shown that increases in cellular free cholesterol levels stimulate apoE transcription in macrophages and adipocytes; however, the molecular basis for this regulation is unknown. Recently, Taylor and colleagues [Shih, S. J., Allan, C., Grehan, S., Tse, E., Moran, C. & Taylor, J. M. (2000) J. Biol. Chem. 275, 31567-31572] identified two enhancers from the human apoE gene, termed multienhancer 1 (ME.1) and multienhancer 2 (ME.2), that direct macrophage- and adipose-specific expression in transgenic mice. We demonstrate here that the nuclear receptors LXRalpha and LXRbeta and their oxysterol ligands are key regulators of apoE expression in both macrophages and adipose tissue. We show that LXR/RXR heterodimers regulate apoE transcription directly, through interaction with a conserved LXR response element present in both ME.1 and ME.2. Moreover, we demonstrate that the ability of oxysterols and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in Lxralpha-/- or Lxrbeta-/- mice and abolished in double knockouts. Basal expression of apoE is not compromised in Lxr null mice, however, indicating that LXRs mediate lipid-inducible rather than tissue-specific expression of this gene. Together with our previous work, these findings support a central role for LXR signaling pathways in the control of macrophage cholesterol efflux through the coordinate regulation of apoE, ABCA1, and ABCG1 expression.
动脉壁中的巨噬细胞分泌的载脂蛋白E（apoE）对动脉粥样硬化的发展具有重要的保护作用，可能是通过其促进脂质流出的能力来实现的。先前的研究表明，细胞内游离胆固醇水平的升高会刺激巨噬细胞和脂肪细胞中apoE的转录；然而，这种调节的分子基础尚不清楚。最近，泰勒及其同事[施，S.J.，艾伦，C.，格雷汉，S.，谢，E.，莫兰，C.和泰勒，J.M.（2000年）《生物化学杂志》275，31567 - 31572]从人类apoE基因中鉴定出两个增强子，称为多增强子1（ME.1）和多增强子2（ME.2），它们在转基因小鼠中指导巨噬细胞和脂肪特异性表达。我们在此证明，核受体LXRα和LXRβ及其氧化甾醇配体是巨噬细胞和脂肪组织中apoE表达的关键调节因子。我们表明，LXR/RXR异二聚体通过与ME.1和ME.2中存在的保守LXR反应元件相互作用直接调节apoE转录。此外，我们证明，在Lxralpha - / - 或Lxrbeta - / - 小鼠中，氧化甾醇和合成配体调节脂肪组织和腹膜巨噬细胞中apoE表达的能力降低，而在双敲除小鼠中则完全丧失。然而，Lxr基因敲除小鼠中apoE的基础表达并未受到影响，这表明LXR介导该基因的脂质诱导而非组织特异性表达。与我们之前的工作一起，这些发现支持LXR信号通路在通过协调调节apoE、ABCA1和ABCG1表达来控制巨噬细胞胆固醇流出中起核心作用。
