Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.
Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.
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DOI：
10.1073/pnas.1714518115
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发表时间：
2018-05-15
影响因子：
11.1
通讯作者：
Glass CK
中科院分区：
文献类型：
--
作者：
Muse ED;Yu S;Edillor CR;Tao J;Spann NJ;Troutman TD;Seidman JS;Henke A;Roland JT;Ozeki KA;Thompson BM;McDonald JG;Bahadorani J;Tsimikas S;Grossman TR;Tremblay MS;Glass CK
LXR途径激活的有益作用早已被认识，但合成LXR配体的临床应用受到SREBP1c共激活和随之而来的高胆固醇血症的限制。天然LXR配体如桥甾醇不促进高胆固醇血症，因为SREBP途径的协同下调。在这里，我们证明了合成的链甾醇模拟物在体外和体内激活巨噬细胞中的LXR，同时抑制SREBP靶基因。出乎意料的是，与常规的合成LXR配体相比，链甾醇和合成链甾醇模拟物对肝细胞中的LXR活性几乎没有影响。这些发现揭示了巨噬细胞和肝细胞中LXR对天然和合成配体反应的细胞特异性差异，为未来药物开发提供了概念上的新基础。在小鼠模型中，用合成激动剂激活肝脏X受体（LXRs）可促进胆固醇逆向转运并防止动脉粥样硬化。大多数合成LXR激动剂也通过诱导固醇调节元件结合蛋白（SREBP）1c和驱动脂肪酸生物合成的下游基因的表达引起显著的高胆固醇血症。最近的研究表明，桥甾醇，胆固醇生物合成途径中的中间体，通过结合SCAP抑制SREBP加工，也结合并激活LXR，是巨噬细胞泡沫细胞中最丰富的LXR配体。在这里，我们探讨了增加内源性桥甾醇产生或模拟其活性作为诱导LXR活性的手段，同时抑制SREBP1c诱导的高胆固醇血症的潜力。出乎意料的是，虽然桥固醇在小鼠和人巨噬细胞中强烈激活LXR靶基因并抑制SREBP途径，但它在体外小鼠或人肝细胞中几乎没有活性。我们进一步证明，基于甾醇的LXR选择性调节剂具有桥甾醇模拟物的生物化学和转录特性，并在体外和体内选择性地调节巨噬细胞中的LXR功能。因此，这些研究揭示了LXR和SREBP的内源性和合成调节剂的细胞特异性区分，为巨噬细胞中的LXR功能与肝脏中导致高脂血症的LXR功能的分离提供了分子基础。
The beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development. Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.
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影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
影响因子：
29
作者：
Kirchgessner, Todd G.;Sleph, Paul;Frost, Robert J. A.
通讯作者：
Frost, Robert J. A.
DOI：
10.1016/0006-291x(60)90266-7
发表时间：
1960-01-01
影响因子：
3.1
作者：
AVIGAN, J;STEINBERG, D;MOSETTIG, E
通讯作者：
MOSETTIG, E
影响因子：
15.9
作者：
Bradley, Michelle N.;Hong, Cynthia;Tontonoz, Peter
通讯作者：
Tontonoz, Peter
DOI：
10.1073/pnas.112059299
发表时间：
2002-05-28
影响因子：
11.1
作者：
Joseph, SB;McKilligin, E;Tontonoz, P
通讯作者：
Tontonoz, P