Down-Regulation of the LXR Transcriptome Provides the Requisite Cholesterol Levels to Proliferating Hepatocytes
Down-Regulation of the LXR Transcriptome Provides the Requisite Cholesterol Levels to Proliferating Hepatocytes
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DOI：
10.1002/hep.23436
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发表时间：
2010-04-01
期刊：
影响因子：
13.5
通讯作者：
Moschetta, Antonio
中科院分区：
文献类型：
--
作者：
Lo Sasso, Giuseppe;Celli, Nicola;Moschetta, Antonio
胆固醇稳态对于细胞增殖至关重要。肝脏 X 受体 (LXR) α 和 β 是负责调节胆固醇代谢的核受体。在生理条件下，高细胞内胆固醇水平会导致氧甾醇合成增加，从而激活 LXR，从而引发胆固醇分泌和分解代谢的转录反应。在这里，我们采用部分肝切除术 (PH) 的小鼠模型来剖析连接胆固醇稳态、细胞增殖和 LXR 的分子途径。首先，我们发现 PH 后肝脏胆固醇含量增加，而整个 LXR 转录组下调。尽管 LXR 信使 RNA (mRNA) 水平未发生改变，但 LXR 靶基因在 PH 后第 1 天显着下调，并在第 7 天肝脏达到正常大小时恢复至对照水平。 PH 后 LXR 失活与合成减少、硫酸化和分泌增加而导致氧甾醇可用性降低有关。相反，胆固醇合成上调，细胞外基质重塑增强。其次，我们表明通过合成配体重新激活 LXR 决定了肝细胞增殖的负调节。这种作用是通过肝脏胆固醇分解代谢和分泌途径的重新激活以及胆固醇生物合成的显着减少来维持的。我们的数据揭示了 LXR 调制之前未被认识且明显矛盾的场景。在肝脏再生过程中，尽管细胞内胆固醇水平增加，但 LXR 活性却减弱。关闭 LXR 转录途径对于保证再生肝细胞所需的细胞内胆固醇水平至关重要。与这一假设相符，PH 期间药物 LXR 重新激活显着降低了肝脏再生能力。 （肝病学 2010；51：1334-1344。）
Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. Here we employed a mouse model of partial hepatectomy (PH) to dissect the molecular pathways connecting cholesterol homeostasis, cellular proliferation, and LXR. First, we show that hepatic cholesterol content increases after PH, whereas the entire LXR transcriptome is down-regulated. Although LXR messenger RNA (mRNA) levels are unmodified, LXR target genes are significantly down-regulated on day 1 after PH and restored to control levels on day 7, when the liver reaches normal size. The inactivation of LXR following PH is related to the reduced oxysterol availability by way of decreased synthesis, and increased sulfation and secretion. On the contrary, cholesterol synthesis is up-regulated, and extracellular matrix remodeling is enhanced. Second, we show that reactivation of LXR by way of a synthetic ligand determines a negative modulation of hepatocyte proliferation. This effect is sustained by the reactivation of hepatic cholesterol catabolic and secretory pathways, coupled with a significant reduction of cholesterol biosynthesis. Our data unveil a previously unrecognized and apparently paradoxical scenario of LXR modulation. During liver regeneration LXR activity is abated in spite of increasing intracellular cholesterol levels. Turning off LXR-transcriptional pathways is crucial to guaranteeing the requisite intracellular cholesterol levels of regenerating hepatocytes. In line with this hypothesis, pharmacological LXR reactivation during PH significantly reduces liver regeneration capacity. (HEPATOLOGY 2010;51:1334-1344.)