甲状腺素受体β基因启动子甲基化调节参与高血压和肥胖的机制研究

The long-term goal of this project is to elucidate the mechanisms that thyroid hormone is involved in hypertension and obesity, two major risk factors of cardiovascular diseases. The cardiovascular system is one of the most important targets of thyroid hormones. So far, several studies have demonstrated a correlation between thyroid function/thyroid hormone levels and hypertension, obesity, dyslipidemia, and some components of metabolic syndrome. But the underlying mechanisms are not fully clarified. Our preliminary results demonstrated that thyroid hormone receptor B-THRB may be involved in this process. We recruited a cohort including 4 groups, hypertension & obesity, hypertension, obesity, and control. Lower TSH levels and lower ratio of free T3 to T3 were found in hypertension and obesity groups. Illumina 450K Beadchip array showed that the methylation was significantly lower in hypertension and obesity groups, which was confirmed by MassArray. We also performed a qualitative analysis. Low methylation status was associated with hypertension and obesity, meanwhile, lower TSH was found in low methylation group. So THRB promoter methylation was associated with hypertension and obesity, which might be served as a novel therapeutic target of hypertension and obesity, or cardiac disease brought by them. These results raise the possibility that T3 treatment for hypertension or obesity induced by THRB abnormal epigenetic regulation. To test this hypothesis, we will determine whether and how THRB overexpression would induce hypertension or obesity. We will also investigate the effective of T3 treatment for hypertension and obesity induced by lower promoter methylation of THRB. Successful completion of this project will .provide novel insight into the mechanisms of hypertension and obesity, thus facilitating drug design for preventing or treating hypertension and obesity.

心血管系统受甲状腺素作用调控。已有研究证明甲状腺功能/甲状腺激素水平与高血压、肥胖、血脂异常等一系列代谢综合征表型密切相关，但机制未明。我们前期研究表明甲状腺素受体β基因THRB的启动子区低甲基化与高血压和肥胖相关。高血压和/或肥胖组显示出低的血清TSH水平及fT3/T3比值，全基因组甲基化芯片筛查显示THRB的启动子区甲基化水平显著低于正常组，而低甲基化组也表现出低的TSH血清水平。因此我们假设THRB的甲基化调节参与了高血压/肥胖的发生发展。在该课题中，我们将首先验证THRB启动子区甲基化调节对其基因表达的影响，利用转基因动物制作高表达模型研究THRB高表达对血压调节及脂肪代谢的影响；进而我们将研究T3补充是否能够预防和/或改善THRB过表达引起的高血压和/或肥胖。该课题的成功实施将为高血压和肥胖的机制提供新视点，为他们的治疗和预防提供新靶点。

代谢综合征(MetS)的人群中会出现甲状腺激素(TH)功能异常，但其机制仍不清楚。基因组甲基化状态改变的与代谢综合征(MetS)密切相关。为确定TH功能相关基因中的甲基化调控是否与MetS有关，在一个严格选择的小队列人群中，通过Illumina 450K芯片进行的全基因组甲基化筛。研究发现MetS组TH功能低下；于此同时，外周血THRB启动子甲基化水平低于对照人群。这一结果在另一个大型队列人群中也得到了验证。研究结果也表明THRB启动子甲基化状态影响其启动子活性进而影响THRB的表达。在高脂高果糖饮食诱导的MetS大鼠模型中也观察到Thrb启动子甲基化水平降低及TH功能低下。此外，发现在MetS中观察到的系统性炎症可诱导THRB启动子低甲基化，进而引起THRB高表达。生理剂量T3口服治疗可降低MetS大鼠的血压和胰岛素抵抗，并部分减轻了肝脏脂肪变性和脂肪细胞肥大等表型。基于以上结果我们认为系统性炎症引起外周血THRB启动子的低甲基化，这一过程与MetS的TH功能低下有关，而TH功能低下使MetS进一步恶化。这一发现可能作为MetS新的治疗靶点。