Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3.
Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3.
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DOI：
10.1016/s0021-9258(19)49613-0
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发表时间：
1992-08
期刊：
影响因子：
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通讯作者：
J. Ladias;M. Hadzopoulou-Cladaras;D. Kardassis;P. Cardot;Jian Cheng;V. Zannis;C. Cladaras;John A. A.
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文献类型：
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作者：
J. Ladias;M. Hadzopoulou-Cladaras;D. Kardassis;P. Cardot;Jian Cheng;V. Zannis;C. Cladaras;John A. A.
载脂蛋白 B、CIII 和 AII 主要在肝脏和肠道中合成，在脂质和胆固醇代谢中发挥重要作用。之前的研究表明，人类 apoB、apoCIII 和 apoAII 基因调控区中分别存在的顺式作用元件（BA1（-79 至 -63）、CIIIB（-87 至 -63）和 AIIJ（-740 至 -719））可被肝核提取物中存在的常见转录因子识别。该报告表明，类固醇受体超家族的四个成员 ARP-1、 EAR-2、EAR-3 和 HNF-4 与调节元件 BA1、CIIIB 和 AIIJ 特异性结合。解离常数测量表明 ARP-1、EAR-2 和 HNF-4 以相似的亲和力 (Kd 1-3 nM) 与元件 BA1 和 CIIIB 结合。HepG2 细胞中的共转染实验表明 ARP-1、EAR-2 和 EAR-3 抑制 BA1、CIIIB 和 AIIJ。报告基因构建体的 CIIIB 和 AIIJ 元件依赖性转录以及由包含 5 个 BA1 或 2 个 CIIIB 元件的同聚启动子驱动的转录相反，HNF-4 激活包含 BA1、CIIIB 和 AIIJ 元件的报告基因的转录，并逆转 ARP-1 介导的 apoB 和 apoCIII 基因的抑制。影响 HNF-4 与元件 BA1 和 CIIIB 结合的突变分别影响其激活 apoB 和 apoCIII 报告基因转录的能力。HNF-4 的转录激活取决于 apoB 元件 II（-112 至 -94）和 III（-86 至 -62）以及 H（-705 至 -690）、I（-766 至 -726）和 J。 (-792 至 -779) 的 apoCIII 启动子，表明 HNF-4 对 apoB 和 apoCIII 基因的转录激活需要与这些元件结合的因子的协同相互作用。HNF-4、ARP-1、EAR-2 和 EAR-3 可以调节 apoB、apoCIII 和 apoAII 基因的表达，这表明这些核激素受体可能是调节信号转导途径的重要部分。脂质代谢和胆固醇稳态。
Apolipoproteins B, CIII, and AII are synthesized primarily in the liver and intestine and play an important role in lipid and cholesterol metabolism. It was previously shown that the cis-acting elements (BA1 (-79 to -63), CIIIB (-87 to -63), and AIIJ (-740 to -719) present in the regulatory regions of the human apoB, apoCIII, and apoAII genes, respectively, are recognized by common transcription factors present in hepatic nuclear extracts. This report shows that four members of the steroid receptor superfamily, ARP-1, EAR-2, EAR-3, and HNF-4, bind specifically to the regulatory elements BA1, CIIIB, and AIIJ. Dissociation constant measurements showed that ARP-1, EAR-2, and HNF-4 bind to elements BA1 and CIIIB with similar affinities (Kd 1-3 nM). Cotransfection experiments in HepG2 cells revealed that ARP-1, EAR-2, and EAR-3 repressed the BA1, CIIIB, and AIIJ element-dependent transcription of the reporter gene constructs and the transcription driven by homopolymeric promoters containing either five BA1 or two CIIIB elements. In contrast, HNF-4 activated transcription of reporter genes containing the elements BA1, CIIIB, and AIIJ and reversed the ARP-1-mediated repression of the apoB and apoCIII genes. These results suggested that the opposing transcription effects observed between HNF-4 and ARP-1 may be due to competition for binding to the same regulatory element. Mutations which affected the binding of HNF-4 to elements BA1 and CIIIB affected its ability to activate transcription of the apoB and apoCIII reporter genes, respectively. Transcriptional activation by HNF-4 depended on the presence of elements II (-112 to -94) and III (-86 to -62) of the apoB and H (-705 to -690), I (-766 to -726), and J (-792 to -779) of the apoCIII promoters, indicating that transcriptional activation of apoB and apoCIII genes by HNF-4 requires the synergistic interaction of factors binding to these elements. The finding that HNF-4, ARP-1, EAR-2 and EAR-3 can regulate the expression of the apoB, apoCIII, and apoAII genes suggest that these nuclear hormone receptors may be an important part of the signal transduction pathways modulating lipid metabolism and cholesterol homeostasis.