van der Krieken Sophie E, Popeijus Herman E, Mensink Ronald P, Plat Jogchum
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, 616-6200, the Netherlands.
J Cell Biochem. 2017 Aug;118(8):2161-2167. doi: 10.1002/jcb.25858. Epub 2017 Apr 18.
Activating transcription factor peroxisome proliferator-activated receptor alpha (PPARα) may increase apoA-I transcription. Furthermore, Bromodomain and Extra-Terminal domain (BET) protein inhibitors increase, whereas Endoplasmic Reticulum (ER) stress decreases apoA-I transcription. We examined possible links between these processes as related to apoA-I transcription in HepG2 cells. JQ1(+), thapsigargin, and GW7647 were used to induce, respectively BET inhibition, ER-stress, and PPARα activation. Expression of ER-stress markers (CHOP, XBP1s) was analyzed by western blotting. PPARα, KEAP1 (marker for BET inhibition), and apoA-I mRNAs were measured using qPCR. ER-stress and BET inhibition both decreased PPARα mRNA expression and activity, but did not interfere with each other, as ER-stress did not change KEAP1 and JQ1(+) did not influence ER-stress marker production. Interestingly, PPARα activation and BET-inhibition diminished ER-stress marker production and rescued apoA-I transcription during existing ER-stress. We conclude that the ER-stress mediated reduction in apoA-I transcription could be partly mediated via the inhibition of PPARα mRNA expression and activity. In addition, BET inhibition increased apoA-I transcription, even if PPARα production and activity were decreased. Finally, both BET inhibition and PPARα activation ameliorate the apoA-I lowering effect of ER-stress and are therefore interesting targets to elevate apoA-I transcription. J. Cell. Biochem. 118:2161-2167, 2017. © 2016 Wiley Periodicals, Inc.
激活转录因子过氧化物酶体增殖物激活受体α（PPARα）可能会增加载脂蛋白A-I（apoA-I）的转录。此外，溴结构域和额外末端结构域（BET）蛋白抑制剂会增加apoA-I的转录，而内质网（ER）应激则会降低其转录。我们研究了这些过程之间与HepG2细胞中apoA-I转录相关的可能联系。使用JQ1（+）、毒胡萝卜素和GW7647分别诱导BET抑制、ER应激和PPARα激活。通过蛋白质免疫印迹分析ER应激标志物（CHOP、XBP1s）的表达。使用定量聚合酶链反应（qPCR）测量PPARα、KEAP1（BET抑制的标志物）和apoA-I的信使核糖核酸（mRNA）。ER应激和BET抑制均降低了PPARα mRNA的表达和活性，但彼此不产生干扰，因为ER应激不会改变KEAP1，而JQ1（+）不会影响ER应激标志物的产生。有趣的是，PPARα激活和BET抑制减少了ER应激标志物的产生，并在现有ER应激期间挽救了apoA-I的转录。我们得出结论，ER应激介导的apoA-I转录减少可能部分是通过抑制PPARα mRNA的表达和活性来介导的。此外，即使PPARα的产生和活性降低，BET抑制也会增加apoA-I的转录。最后，BET抑制和PPARα激活均改善了ER应激对apoA-I的降低作用，因此是提高apoA-I转录的有趣靶点。《细胞生物化学杂志》118:2161 - 2167，2017年。©2016威利期刊公司
