Rottman J N, Widom R L, Nadal-Ginard B, Mahdavi V, Karathanasis S K
Department of Cardiology, Children's Hospital, Boston, Massachusetts.
Mol Cell Biol. 1991 Jul;11(7):3814-20. doi: 10.1128/mcb.11.7.3814-3820.1991.
The gene coding for apolipoprotein AI, a plasma protein involved in the transport of cholesterol and other lipids in the plasma, is expressed predominantly in liver and intestine. Previous work in our laboratory has shown that hepatocyte-specific expression is determined by synergistic interactions between transcription factors bound to three separate sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within a powerful liver-specific enhancer located in the region -222 to -110 nucleotides upstream of the apolipoprotein AI gene transcription start site (+1). In this study, it was found that site A is a highly selective retinoic acid-responsive element (RARE) that responds preferentially to the recently identified retinoic acid receptor RXR alpha over the previously characterized retinoic acid receptors RAR alpha and RAR beta. Control experiments indicated that a RARE in the regulatory region of the laminin B1 gene responds preferentially to RAR alpha and RAR beta over RXR alpha, while a previously described palindromic thyroid hormone-responsive element responds similarly to all three of these receptors. Gel retardation experiments showed that the activity of these RAREs is concordant with receptor binding. These results indicate that different RAREs may play a fundamental role in defining distinctive retinoic acid cellular response pathways and suggest that retinoic acid response pathways mediated by RXR alpha play an important role in cholesterol and retinoid transport and metabolism.
载脂蛋白AI是一种参与血浆中胆固醇及其他脂质运输的血浆蛋白，编码该蛋白的基因主要在肝脏和肠道中表达。我们实验室之前的研究表明，肝细胞特异性表达是由结合在三个独立位点上的转录因子之间的协同相互作用决定的，这三个位点分别是A位点（-214至-192）、B位点（-169至-146）和C位点（-134至-119），它们位于载脂蛋白AI基因转录起始位点（+1）上游-222至-110核苷酸区域内一个强大的肝脏特异性增强子中。在本研究中，发现A位点是一个高度选择性的视黄酸反应元件（RARE），与之前鉴定的视黄酸受体RARα和RARβ相比，它对最近鉴定出的视黄酸受体RXRα反应更为优先。对照实验表明，层粘连蛋白B1基因调控区域中的一个RARE对RARα和RARβ的反应比对RXRα更为优先，而先前描述的回文甲状腺激素反应元件对这三种受体的反应相似。凝胶阻滞实验表明，这些RARE的活性与受体结合情况一致。这些结果表明，不同的RARE可能在定义独特的视黄酸细胞反应途径中起重要作用，并提示由RXRα介导的视黄酸反应途径在胆固醇和类视黄醇的运输及代谢中起重要作用。
