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首页> 外文期刊>Molecular and Cellular Biology >Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor.
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Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor.

机译：维甲酸通过激活维甲酸X受体而不是维甲酸受体来增加人载脂蛋白A-11的表达。

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Considering the link between plasma high-density lipoprotein (HDL) cholesterol levels and a protective effect against coronary artery disease as well as the suggested beneficial effects of retinoids on the production of the major HDL apolipoprotein (apo), apo A-I, the goal of this study was to analyze the influence of retinoids on the expression of apo A-II, the other major HDL protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II secretion in primary cultures of human hepatocytes. In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection experiments with a reporter construct driven by the human apo A-II gene promoter indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG 100268, induced apo A-II gene expression at the transcriptional level. Only minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter reporter construct. Unilateral deletions and site-directed mutagenesis identified the J site of the apo A-II promoter mediating the responsiveness to RA. This element contains two imperfect half-sites spaced by 1 oligonucleotide. Cotransfection assays in combination with the use of RXR or RAR agonists showed that RXR but not RAR transactivates the apo A-II promoter through this element. By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR response element. In conclusion, retinoids induce hepatic apo A-II production at the transcriptional level via the interaction of RXR with an element in the J site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby demonstrating an important role of RXR in controlling human lipoprotein metabolism. Since the J site also confers responsiveness of the apo A-II gene to fibrates and fatty acids via the activation of peroxisome proliferator-activated receptor-RXR heterodimers, this site can be considered a plurimetabolic response element.
机译：考虑到血浆高密度脂蛋白（HDL）胆固醇水平与对冠状动脉疾病的保护作用之间的联系，以及类维生素A对主要HDL载脂蛋白（apo），apo AI产生的建议的有益作用，此目标这项研究旨在分析类维生素A对另一种主要HDL蛋白apo A-II表达的影响。视黄酸（RA）衍生物对肝脏载脂蛋白A-II的产生有直接影响，因为全反式RA诱导人肝细胞原代培养物中载脂蛋白A-II mRNA的水平和载脂蛋白A-II的分泌。在HepG2人肝母细胞瘤细胞系中，at-RA和9-顺式RA以及类视色素X受体（RXR）特异性激动剂LGD 1069，但不包括RA受体（RAR）激动剂乙基-p-[[E] -2-（5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基）-1-原戊基]-苯甲酸（TTNPB）诱导apo A-II mRNA水平。使用由人类载脂蛋白A-II基因启动子驱动的报告基因构建体进行的瞬时转染实验表明，9-顺式RA和at-RA以及RXR激动剂LGD 1069和LG 100268诱导了载脂蛋白A-II基因的表达。转录水平。在载脂蛋白A-II启动子报告基因构建体上仅观察到RAR激动剂TTNPB的最小作用。单方面的删除和定点诱变确定了载脂蛋白A-II启动子的J位点介导对RA的反应。该元件包含两个不完美的半位点，由1个寡核苷酸隔开。共转染测定结合RXR或RAR激动剂的使用表明，RXR（但不是RAR）通过该元件激活apo A-II启动子。相比之下，RAR以剂量依赖性方式抑制RXR对apo A-II J位点的诱导作用。凝胶阻滞分析表明，尽管亲和力比RAR-RXR异二聚体低，但RXR同二聚体与AH-RXR反应元件结合。总之，类维生素A通过RXR与J位点中的元素相互作用而在转录水平上诱导肝载脂蛋白A-II的产生，该J位点包含两个由1个寡核苷酸隔开的不完美的半位点，从而证明了RXR在控制人脂蛋白代谢中的重要作用。由于J位点还通过过氧化物酶体增殖物激活的受体-RXR异二聚体的活化而赋予了载脂蛋白A-II基因对纤维蛋白和脂肪酸的响应性，因此该位点可以被认为是多代谢反应元件。

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