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Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.bbalip.2019.158583
Yan Liu 1 , Lahoucine Izem 1 , Richard E Morton 1
Affiliation  

Apolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPARα nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and 4 potential PPARα binding sites clustered between nucleotides -2007 and -1961. ChIP analysis confirmed agonist-dependent binding of LXRα, PPARα, and RXRα to this hormone response element complex (HREc). A luciferase reporter containing the 2 kb 5' APOF sequence was negatively regulated by LXR and PPARα ligands as seen in cells. This regulation was maintained in constructs lacking the ~1700 nucleotides between the HREc and the APOF proximal promoter. Mutations of the HREc that disrupted LXRα and PPARα binding led to the loss of reporter construct inhibition by agonists of these nuclear receptors. siRNA knockdown studies showed that APOF gene regulation by LXRα or PPARα agonists did not require an interaction between these two nuclear receptors. Thus, APOF is subject to negative regulation by agonist-activated LXR or PPARα nuclear receptors binding to a regulatory element ~1900 bases 5' to the APOF promoter. High fat, cholesterol-enriched diets likely reduce APOF gene expression via these receptors interacting at this regulatory site.

中文翻译:

鉴定介导LXR和PPARα激动剂抑制APOF的激素反应元件。

载脂蛋白F(ApoF)调节胆固醇酯转移蛋白的活性。我们先前观察到高脂肪,高胆固醇饮食会降低肝脏APOF mRNA水平。在这里,我们显示了在人肝C3A细胞中,APF mRNA水平被LXR和PPARα核受体激动剂降低了。这种负调控需要与RXR激动剂视黄酸共同孵育。对APOF启动子上游〜2 kb序列的生物信息学分析确定了一个潜在的LXR和4个潜在的PPARα结合位点,聚集在核苷酸-2007和-1961之间。ChIP分析证实了LXRα,PPARα和RXRα与该激素反应元件复合物(HREc)的激动剂依赖性结合。如在细胞中所见,包含2 kb 5'APOF序列的荧光素酶报道分子受到LXR和PPARα配体的负调控。在HREc和APOF近端启动子之间缺少〜1700个核苷酸的构建体中维持了这种调节。破坏LXRα和PPARα结合的HREc突变导致这些核受体激动剂失去了对报告基因构建体的抑制作用。siRNA敲低研究表明,LXRα或PPARα激动剂对APOF基因的调控不需要这两个核受体之间的相互作用。因此,APOF受到激动剂激活的LXR或PPARα核受体的负调节,所述LXR或PPARα核受体与APOF启动子的约1900个碱基的5'端结合。高脂肪,富含胆固醇的饮食可能通过这些受体在此调节位点相互作用而降低了APOF基因的表达。破坏LXRα和PPARα结合的HREc突变导致这些核受体激动剂失去了对报告基因构建体的抑制作用。siRNA敲低研究表明,LXRα或PPARα激动剂对APOF基因的调控不需要这两个核受体之间的相互作用。因此,APOF受到激动剂激活的LXR或PPARα核受体的负调控,所述LXR或PPARα核受体与APOF启动子的约1900个碱基的5'端结合。高脂肪,高胆固醇饮食可能会通过这些受体在此调节位点相互作用而降低APOF基因的表达。破坏LXRα和PPARα结合的HREc突变导致这些核受体激动剂失去了对报告基因构建体的抑制作用。siRNA敲低研究表明,LXRα或PPARα激动剂对APOF基因的调控不需要这两个核受体之间的相互作用。因此,APOF受到激动剂激活的LXR或PPARα核受体的负调节,所述LXR或PPARα核受体与APOF启动子的约1900个碱基的5'端结合。高脂肪,富含胆固醇的饮食可能通过这些受体在此调节位点相互作用而降低了APOF基因的表达。因此,APOF受到激动剂激活的LXR或PPARα核受体的负调节,所述LXR或PPARα核受体与APOF启动子的约1900个碱基的5'端结合。高脂肪,富含胆固醇的饮食可能通过这些受体在此调节位点相互作用而降低了APOF基因的表达。因此,APOF受到激动剂激活的LXR或PPARα核受体的负调节,所述LXR或PPARα核受体与APOF启动子的约1900个碱基的5'端结合。高脂肪,富含胆固醇的饮食可能通过这些受体在此调节位点相互作用而降低了APOF基因的表达。
更新日期:2019-12-06
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