Dhar-Mascareno Manya, Rozenberg Inna, Iqbal Jahangir, Hussain M Mahmood, Beckles Daniel, Mascareno Eduardo
Department of Biological Sciences, State University of New York, College at Old Westbury, Old Westbury, New York 11568, USA.
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York, 11203 USA.
Int J Biochem Cell Biol. 2017 Feb;83:56-64. doi: 10.1016/j.biocel.2016.12.010. Epub 2016 Dec 21.
Hexim-1 is an inhibitor of RNA polymerase II transcription elongation. Decreased Hexim-1 expression in animal models of chronic diseases such as left ventricular hypertrophy, obesity and cancer triggered significant changes in adaptation and remodeling. The main aim of this study was to evaluate the role of Hexim1 in lipid metabolism focused in the progression of atherosclerosis and steatosis. We used the C57BL6 apolipoprotein E (ApoE null) crossed bred to C57BL6Hexim1 heterozygous mice to obtain ApoE null - Hexim1 heterozygous mice (ApoE-HT). Both ApoE null backgrounds were fed high fat diet for twelve weeks. Then, we evaluated lipid metabolism, atherosclerotic plaque formation and liver steatosis. In order to understand changes in the transcriptome of both backgrounds during the progression of steatosis, we performed Affymetrix mouse 430 2.0 microarray. After 12 weeks of HFD, ApoE null and ApoE-HT showed similar increase of cholesterol and triglycerides in plasma. Plaque composition was altered in ApoE-HT. Additionally, liver triglycerides and steatosis were decreased in ApoE-HT mice. Affymetrix analysis revealed that decreased steatosis might be due to impaired inducible SOCS3 expression in ApoE-HT mice. In conclusion, decreased Hexim-1 expression does not alter cholesterol metabolism in ApoE null background after HFD. However, it promotes stable atherosclerotic plaque and decreased steatosis by promoting the anti-inflammatory TGFβ pathway and blocking the expression of the inducible and pro-inflammatory expression of SOCS3 respectively.
Hexim-1是RNA聚合酶II转录延伸的抑制剂。在诸如左心室肥大、肥胖和癌症等慢性疾病的动物模型中，Hexim-1表达降低引发了适应性和重塑方面的显著变化。本研究的主要目的是评估Hexim1在脂质代谢中的作用，重点关注动脉粥样硬化和脂肪变性的进展。我们将C57BL6载脂蛋白E（ApoE基因敲除）小鼠与C57BL6Hexim1杂合小鼠杂交，以获得ApoE基因敲除 - Hexim1杂合小鼠（ApoE-HT）。两种ApoE基因敲除背景的小鼠均喂食高脂饮食12周。然后，我们评估了脂质代谢、动脉粥样硬化斑块形成和肝脏脂肪变性。为了了解脂肪变性进展过程中两种背景小鼠转录组的变化，我们进行了Affymetrix小鼠430 2.0微阵列分析。高脂饮食12周后，ApoE基因敲除小鼠和ApoE-HT小鼠血浆中的胆固醇和甘油三酯均有类似程度的升高。ApoE-HT小鼠的斑块组成发生了改变。此外，ApoE-HT小鼠肝脏中的甘油三酯和脂肪变性有所减少。Affymetrix分析显示，脂肪变性减少可能是由于ApoE-HT小鼠中诱导型SOCS3表达受损所致。总之，高脂饮食后，Hexim-1表达降低在ApoE基因敲除背景下不会改变胆固醇代谢。然而，它通过分别促进抗炎性TGFβ途径和阻断诱导型及促炎性SOCS3的表达，促进了稳定的动脉粥样硬化斑块形成并减少了脂肪变性。
