非酒精性脂肪肝（NAFLD）主要特征是肝内甘油三酯蓄积。临床资料显示TSH水平与NAFLD 患病率呈正相关，但机制不明。课题组前期研究发现肝脏表达有生物活性的TSH受体（TSHR）；TSH增加肝细胞固醇调节元件结合蛋白-1c(SREBP-1c)的表达和甘油三酯含量；高脂喂养的Tshr基因敲除小鼠肝脏脂肪变减轻。目前关于TSH调节肝脏甘油三酯合成的研究未见国内外报道。本项目以TSH为切入点,围绕调节肝脏甘油三酯合成的关键分子SREBP-1c,应用体内动物（条件性敲除甲状腺Tshr基因、条件性敲除肝脏Tshr基因、SREBP-1c基因敲除、PPARα基因敲除小鼠等多种模型）与体外细胞水平（TSH刺激肝细胞、沉默基因表达及阻断传递等技术）相结合技术手段，阐明TSH通过肝脏TSHR和SREBP-1c介导增加甘油三酯合成的作用及机制，为揭示TSH在NAFLD发生发展中的作用提供新思路。

Non-alcoholic fatty liver disease (NAFLD) is a risk factor for cardiovascular diseases. Hallmarks of NAFLD are increased triglyceride accumulation within hepatocytes. Subclinical hypothyroidism (SCH), characterized by an elevated thyrotropin (TSH) level and a normal free thyroxine (T4) level, has recently been demonstrated as a risk factor for NAFLD. Emerging evidence revealed that the prevalence of NAFLD increases steadily with increasing TSH levels. As TSH is the only thyroid function component affected in SCH, it raises the question that whether TSH might also plays an important role in the development of NAFLD. Sterol regulatory element binding protein 1c (SREBP-1c) is a key lipogenic transcription factor, which directly activates the expression of more than 30 genes, dedicated to the synthesis and uptake of fatty acids and triglyceride. Increased SREBP-1c levels were found in patients with histologically diagnosed NAFLD. Our previous study suggested that functional TSH receptor (TSHR) is presented on hepatocyte membrane, through which TSH increases the liver triglyceride content, and ultimately promotes the development of NAFLD. Additionally, our latest reports showed that compared with wild type (Tshr+/+) mice, Tshr-/- mice exhibit a relatively lower degree of liver steatosis and SREBP-1c mRNA expression induced through a high fat diet. Whether SREBP-1c also takes part in the process of TSH regulates hepatic triglyceride and the exact functional mechanisms are still uncertain, and no one once had taken a relative investigation. Therefore, using both in vitro (TSH stimulation on liver cells, interference, blocking or activation of the key molecules) and in vivo (conditionally knockout of liver Tshr gene mouse model, TSHR-RNAi mouse model, thyroid total resection rat model) experiments and the relative key targets intervention approaches, we will elucidate the key molecules and major signaling networks about the effection of TSH on SREBP-1c in the liver, explore the pathophysioligical mechanism of the triglyceride metabolism abnormalities in thyroidal dysfunction situation and further provide newly theoretical evidence for its treatment strategy.