促甲状腺激素通过调控VLDL的分泌和清除影响肝脏与循环间甘油三酯平衡的机制研究

肝脏与循环间的甘油三酯（TG）代谢在生理状态下处于动态平衡。多项研究显示促甲状腺激素（TSH）能促进肝脏TG从头合成，并增加肝脏分泌VLDL。我们前期研究也发现TSH升高人群血清TG水平亦升高，并且TSH不仅能增加肝脏神经酰胺含量，而且可促进肝细胞合成分泌PCSK9促进脂蛋白受体的降解。这提示TSH在调节肝脏与循环间TG平衡中可能扮演重要角色。据此我们提出科学假说：1）TSH增加肝脏神经酰胺生成影响VLDL颗粒组装和分泌，使肝脏向循环输出TG增多；2）TSH上调肝脏合成分泌PCSK9，促进肌肉、脂肪细胞表面VLDL摄取相关受体的降解，阻碍循环中VLDL被摄取利用。为验证这一假说，本项目从人群、大鼠及细胞模型水平，采用脂质组学、色谱分离等技术，探究TSH通过调控VLDL分泌和清除影响肝脏与循环间TG代谢平衡的分子机制，以期为TG代谢异常性疾病（甲减相关NAFLD）寻找到新的治疗靶点和方法。

Circulating VLDL particles encompassing TG are synthesized and secreted by liver to meet the need of the consumption of body organs. Meanwhile, TG clearance could be achieved by eliminating circulating VLDL which is also regulated by the liver. Under physiological condition, TG levels in between the liver and circulation maintain homeostasis. Multiple studies have shown that abnormally elevated thyroid stimulating hormone (TSH) promotes de novo synthesis of TG in liver with an increase in VLDL secretion. Consistently, we found that serum TG level is higher in people with elevated TSH. TSH not only promotes ceramide by upregulating enzymes that are involved in ceramogenesis, but also induces hepatocyte to synthesize and secrete PCSK9 which mediates the degradation of receptors required for VLDL uptake of muscle and adipose tissues. This suggests that TSH may play an important role in balancing TG level between the liver and circulation. Based on this, we propose a scientific hypothesis: 1) TSH promotes biogenesis of ceramide in the liver, leading to increased VLDL particle assembly and secretion, causing higher TG level in circulating system; 2) TSH antagonizes VLDL uptake related receptors by upregulating hepatic synthesis and secretion of PCSK9, leading to decreased VLDL clearance. In order to verify this hypothesis, we will use populations and rats with enhanced serum TSH levels as research objects, using liquid-linked mass spectrometry and lipidomics techniques to explore the role of TSH in the TG metabolic balance between the liver and circulation by regulating VLDL secretion and clearance. This project may provide new therapeutic targets for TG metabolic abnormalities arose from abnormal high TSH levels.