Autoregulation of the human liver X receptor α promoter
Autoregulation of the human liver X receptor α promoter
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DOI：
10.1128/mcb.21.22.7558-7568.2001
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发表时间：
2001-11-01
影响因子：
5.3
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
--
作者：
Laffitte, BA;Joseph, SB;Tontonoz, P
以前的工作表明，核受体LXRα(LXRα)和LXRβ参与了氧化脂质对巨噬细胞基因表达的调节。巨噬细胞脂质负荷导致LXRs的配体激活，并诱导涉及LXR靶基因ABCA1和apoE的胆固醇外流途径。我们在此论证了LXRα基因的自动调节是人类巨噬细胞脂诱导外排途径的重要组成部分。氧化低密度脂蛋白、氧化甾醇和合成的LXR配体诱导人单核细胞来源的巨噬细胞和人巨噬细胞系表达LXRα，但不能诱导小鼠腹膜巨噬细胞或细胞系表达LXRα。这与过氧化物酶体增殖物激活受体γ(PPARγ)特异性配体形成鲜明对比，后者刺激人和小鼠巨噬细胞中LXRα的表达。我们进一步证明，LXR和PPARγ配体协同诱导人巨噬细胞表达LXRα，但不诱导小鼠巨噬细胞表达LXRα。对人LXRα启动子的分析导致了多个LXR反应元件的鉴定。有趣的是，以前在小鼠LXRα基因中发现的PPAR反应元件(PPRE)在人类中不是保守的；然而，在人类LXR 5‘侧翼区域中存在不同的PPRE。这些结果对人巨噬细胞的胆固醇代谢及其受合成的LXR和/或PPAR伽马配体调节的可能性有一定的意义。LXRα调节其自身启动子的能力可能是巨噬细胞对脂质负荷的生理反应的组成部分。
Previous work has implicated the nuclear receptors liver X receptor alpha (LXR alpha) and LXR beta in the regulation of macrophage gene expression in response to oxidized lipids. Macrophage lipid loading leads to ligand activation of LXRs and to induction of a pathway for cholesterol efflux involving the LXR target genes ABCA1 and apoE. We demonstrate here that autoregulation of the LXR alpha gene is an important component of this lipid-inducible efflux pathway in human macrophages. Oxidized low-density lipoprotein, oxysterols, and synthetic LXR ligands induce expression of LXR alpha mRNA in human monocyte-derived macrophages and human macrophage cell lines but not in murine peritoneal macrophages or cell lines. This is in contrast to peroxisome proliferator-activated receptor gamma (PPAR gamma)-specific ligands, which stimulate LXR alpha expression in both human and murine macrophages. We further demonstrate that LXR and PPAR gamma ligands cooperate to induce LXR alpha expression in human but not murine macrophages. Analysis of the human LXR alpha promoter led to the identification of multiple LXR response elements. Interestingly, the previously identified PPAR response element (PPRE) in the murine LXR alpha gene is not conserved in humans; however, a different PPRE is present in the human LXR 5'-flanking region. These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPAR gamma ligands. The ability of LXR alpha to regulate its own promoter is likely to be an integral part of the macrophage physiologic response to lipid loading.