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首页> 外文期刊>Molecular and Cellular Biology >Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice
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Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice

机译：小鼠肝脏X受体介导的肝脏脂质代谢所需的激活信号共整合子2

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摘要

Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXRα?/? mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRα in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.
机译：激活信号共积分器2（ASC-2）是一种癌放大的核受体和许多其他转录因子的转录共激活剂，包含两个LXXLL型核受体相互作用域。有趣的是，第二个LXXLL基序对肝X受体（LXRs）具有高度特异性。在共转染中，DN2（一种包含该基序的ASC-2片段）对LXR的反式激活具有显着的显性负作用，而全长ASC-2的异位共表达可以挽救LXR的反式激活作用，而其他LXXLL型共激活剂则不能作为SRC-1和TRAP220。相反，其中LXXLL基序突变为LXXAA以消除与LXR的相互作用的DN2 / m没有任何作用。因此，在转基因小鼠中表达DN2，而不是DN2 / m，导致其表型与以前用LXRαα/β小鼠观察到的表型高度同源，包括大量胆固醇和蛋白的快速积累。喂高胆固醇饮食后，肝脏中已知的LXRα脂质代谢靶基因下调。这些结果确定了ASC-2是LXRs的重要生理转录共激活因子，并证明了其在肝脂质代谢中的关键作用。

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