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

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.

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。

本项目立意从人民健康需求出发，流行病学研究显示以促甲状腺激素轻度升高、三碘原氨酸和甲状腺素水平正常为特征的亚临床甲状腺功能减退症是非酒精性脂肪性肝病和心脑血管疾病的独立危险因素。我们团队既往发现亚临床甲减女性患者血清甘油三酯水平显著高于对照组。为了探究促甲状腺激素对甘油三酯代谢是否具有调控作用，本项目主要围绕以下内容开展研究工作：构建了促甲状腺激素水平可调控的大鼠模型；在甲减和亚临床甲减的人群及大鼠模型中论证促甲状腺激素促进肝脏分泌极低密度脂蛋白颗粒、增加肝脏向循环输出甘油三酯的具体机制；解析促甲状腺激素水平的升高对脂肪组织等肝外代谢器官的影响。构建促甲状腺激素可调控的大鼠模型时设置了低中高三个梯度促甲状腺激素升高组别，高水平组促甲状腺激素水平与甲状腺术后甲状腺功能减退组水平相当，梯度合理，模型产生的结果具有推广借鉴价值。针对大鼠模型的表型研究发现各促甲状腺激素补充组大鼠体重明显高于对照组，表现为附睾旁脂肪、肠系膜脂肪、腹膜后脂肪等明显增多，肝脏内脂质积累也随着促甲状腺激素水平的增加而增加，血浆中甘油三酯及胆固醇水平同样相应增加。此外，促甲状腺激素促进脂质积累的作用在小鼠AML12细胞系中得到验证。进一步机制研究发现不同浓度外源性促甲状腺激素主要通过调节肝脏脂质合成代谢和脂质分泌影响AML12细胞甘油三酯代谢。本项目的主要发现将加深人们对促甲状腺激素调控肝脏及循环甘油三酯代谢作用的认识，从机制上理解具体的病理生理过程，指导临床医生以系统整体观兼顾治疗促甲状腺激素升高与血脂异常。