Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha.
Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha.
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发表时间：
2000
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通讯作者：
K. A. Tobin;H. H. Steineger-H.;S. Alberti;O. Spydevold;J. Auwerx;J. Gustafsson;H. Nebb
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作者：
K. A. Tobin;H. H. Steineger-H.;S. Alberti;O. Spydevold;J. Auwerx;J. Gustafsson;H. Nebb
LXR α（肝脏X受体，也称为RLD-1）是一种核受体，在脂质稳态中起作用的组织中高度表达。在这份报告中，我们表明，脂肪酸是LXR α基因表达的正调控因子，我们研究了这种调控的分子机制。在培养的大鼠肝癌和原代肝细胞中，脂肪酸和硫取代的脂肪酸类似物十四烷基硫代乙酸强烈诱导LXR α（分别高达3.5倍和7倍），但不诱导LXR β（也称为OR-1）mRNA稳态水平，不饱和脂肪酸比饱和脂肪酸更有效。RNA稳定性和核运行研究表明，LXR α基因转录速率的变化是诱导LXR α mRNA水平的主要原因。用相同的脂肪酸处理原代肝细胞后，也观察到类似的蛋白质水平诱导。与这种转录效应一致，用荧光素酶报告基因进行的瞬时转染研究，由小鼠（m）LXR α基因的1.5kb的5 ′-侧翼区驱动，显示在用十四烷基硫代乙酸和合成的过氧化物酶体增殖物激活受体-α激活剂Wy 14.643处理后，荧光素酶活性的过氧化物酶体增殖物激活受体-α依赖性增加，这表明mLXR α 5 ′侧翼区含有脂肪酸反应性所必需的序列元件。此外，体内LXR α表达由脂肪酸诱导，与体外细胞培养数据一致。这些观察结果表明，LXR α表达受脂肪酸信号通路控制，并表明脂肪酸和胆固醇调节脂质代谢之间存在重要的相互作用。
LXR alpha (liver X receptor, also called RLD-1) is a nuclear receptor, highly expressed in tissues that play a role in lipid homeostasis. In this report we show that fatty acids are positive regulators of LXR alpha gene expression and we investigate the molecular mechanisms underlying this regulation. In cultured rat hepatoma and primary hepatocyte cells, fatty acids and the sulfur-substituted fatty acid analog, tetradecylthioacetic acid, robustly induce LXR alpha (up to 3.5- and 7-fold, respectively) but not LXR beta (also called OR-1) mRNA steady state levels, with unsaturated fatty acids being more effective than saturated fatty acids. RNA stability and nuclear run-on studies demonstrate that changes in the transcription rate of the LXR alpha gene account for the major part of the induction of LXR alpha mRNA levels. A similar induction of protein level was also seen after treatment of primary hepatocytes with the same fatty acids. Consistent with such a transcriptional effect, transient transfection studies with a luciferase reporter gene, driven by 1.5 kb of the 5'-flanking region of the mouse (m)LXR alpha gene, show a peroxisome proliferator-activated receptor-alpha-dependent increase in luciferase activity upon treatment with tetradecylthioacetic acid and the synthetic peroxisome proliferator-activated receptor-alpha activator, Wy 14.643, suggesting that the mLXR alpha 5'-flanking region contains the necessary sequence elements for fatty acid responsiveness. In addition, in vivo LXR alpha expression was induced by fatty acids, consistent with the in vitro cell culture data. These observations demonstrate that LXR alpha expression is controlled by fatty acid signaling pathways and suggest an important cross-talk between fatty acid and cholesterol regulation of lipid metabolism.