TR4翻译后修饰与宫内发育迟缓大鼠代谢综合征的易感机制

Metabolic syndrome (MS) is a given set of disorders with insulin resistance as the core symptom. Inflammation, glucose and lipid metabolism disorders play critical role in the development of MS. Intrauterine growth retardation (IUGR) will increase the risk of adult MS onset. The mechanism involves in epigenetics, but so far it is poorly understood. Testicular nuclear receptor 4 (TR4) involves in many physiological functions, such as growth, development and metabolism, via modulating the transcription of target genes. Our previous study discovered that the TR4 knockout mice were resistant to obesity and the development of MS by increasing energy expenditure and reducing system inflammation. Some studies found that the acetylation in the DNA-binding domain of TR4 could modulate the transcription activity of TR4, and the different sites of post-translational modification (PTM) have different effects on nuclear receptor transcriptional activity. Our hypothesis is that the PTM in the different extent, methods and sites of TR4 is the initial causal of the susceptibility of MS in IUGR population. In this study, we will build aged MS model using IUGR newborn rat, and detect gene expression, protein expression and PTM of TR4 (quantity and site) with RT-PCR, Western blot, immunoaffinity and liquid chromatography tandem mass spectrometry (LC-MS/MS) to prove our hypothesis at molecular, cell, tissue and the whole body level. We would like to explain the epigenetic mechanism of the susceptibility of MS in IUGR population from a new viewpoint of TR4 and provide new targets and timing for the treatment and prevention of MS.

代谢综合征(MS)是一组以胰岛素抵抗(IR)为核心症状的症候群，糖脂代谢紊乱及组织炎症是其关键病因。宫内发育迟缓(IUGR)患者成人期MS易感性增加，其机制涉及表观遗传学改变，但尚需进一步研究阐明。核受体TR4通过调控靶基因的转录从而调节糖和脂质代谢等生理功能。我们研究发现，TR4基因敲除小鼠代谢加速、组织炎症减轻，从而抑制MS的发生。文献报道TR4的转录活性可在翻译后水平受乙酰化修饰的调节；且不同位点的翻译后修饰对核受体转录活性具有不同的调控作用。由此我们假设：TR4不同方式、位点及程度的翻译后修饰是IUGR易感MS的始动因素。本项目将利用IUGR大鼠制备MS模型，采用RT-PCR、Western blot、免疫亲和法及液相串联质谱等技术，从分子、组织及整体水平验证这一假说，阐明定量或定位的TR4翻译后修饰在IUGR大鼠易感MS中的作用，为临床治疗及预防MS提供新的靶点和时机。

代谢综合征(MS)是一组以胰岛素抵抗为核心症状的症候群，糖脂代谢紊乱及组织炎症是其关键病因。宫内发育迟缓(IUGR)患者成人期MS易感性增加，其机制涉及表观遗传学改变。核受体TR4通过调控靶基因的转录从而调节生长发育和代谢等生理功能。文献报道DNA结合区域的乙酰化修饰可降低其转录活性。本项目利用IUGR大鼠制备MS模型，采用RT-PCR、Western blot、免疫亲和法及液相串联质谱等技术，证实IUGR大鼠发生不同程度的糖脂代谢紊乱，以成年期及老年期为甚；调节糖脂代谢的相关细胞因子如CD36、Cide A、Cide C、PPARϒ及炎症因子TNFα的mRNA及蛋白表达均显著增加；TR4作为上游核转录调控因子，其基因、蛋白表达增加，同时其乙酰化修饰水平降低。由此我们认为：IUGR大鼠的肝细胞TR4通过表达量的增加及去乙酰化修饰两条途径增加其转录活性，从而导致下游相关基因表达增加，是IUGR大鼠易感MS的始动因素。本项目从分子、细胞、组织及整体水平阐明TR4乙酰化修饰在IUGR大鼠易感MS中的作用，为临床治疗及预防MS提供新的靶点和时机。