促甲状腺激素（TSH）因增加低密度脂蛋白胆固醇（LDL-c）水平和心血管疾病风险日益受到重视。TSH可直接促进肝脏胆固醇从头合成，而是否影响LDL-c的清除尚不清楚。前蛋白转化酶枯草溶菌素9（PCSK9）经降解LDL受体增加LDL-c水平。我们前期发现亚临床甲减患者（TSH升高，fT3、fT4正常）血清PCSK9水平明显升高；细胞实验证实重组人TSH刺激HepG2细胞，PCSK9 mRNA和蛋白水平均显著上调，胆固醇调节元件结合蛋白（SREBP）-1c、SREBP-2、肝脏X受体（LXR）等也均上调。由此我们提出科学假说：TSH经上调肝细胞PCSK9促进LDL受体降解，增加LDL-c水平。具体机制可能为TSH直接经SREBP增加PCSK9表达，或间接经LXR通路、PCSK9降解途径发挥作用。本研究从PCSK9这个新靶点揭示TSH致胆固醇代谢紊乱的机制，为预防和早期诊治心血管疾病提供新靶点。

Thyroid stimulating hormone (TSH) receives more attention for increasing low density lipoprotein (LDL-c) level and atherosclerotic risk. TSH may induce cholesterol de novo synthesis in hepatocytes. However, whether TSH influence LDL-c metabolism remains unclear. Proprotein convertase subtilisin kexin (PCSK9) mediates LDLR degradation on the surface of hepatocytes, leading to increased LDL-c level. We previously found that plasma PCSK9 level is significantly increased in subclinical hypothyroidism patients only presented with higher TSH level, when compared with controls. In vitro study showed PCSK9 mRNA and protein expression were synchronously up-regulated in HepG2 cells after recombinant human TSH treatment. Besides, sterol regulatory element binding protein (SREBP)-1c, SREBP-2 and liver X receptor (LXR) were also increased after TSH treatment. Therefore comes our hypothesis that TSH may increase hepatic PCSK9 expression and secretion, promoting LDL receptor degradation and leading to higher LDL-c level. We further screened relative signaling pathways and raise some possible mechanisms for the effect of TSH on PCSK9: (1) via SREBPs directly enhancing promotor activity; (2) via LXR pathway activation and PCSK9 degradation indirectly up-regulating PCSK9 level. This project focuses on the new regulating role of TSH on hepatic PCSK9 expression, aimed at providing more evidences to indicate the effect of TSH on lipid metabolism. This project may also help finding a new screening and treatment target for cardiovascular disease.