TSH通过ApoB介导增加肝脏VLDL输出的分子机制

High plasma levels of low-density lipoproteins (LDL-C) and very low-density lipoproteins (VLDL) have been shown to be associated with an increased risk of atherosclerosis, which is the major cause of cardiovascular disease worldwide. Understanding the regulation of their assembly and secretion is of considerable interest. 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 elevated LDL-C. Emerging evidence revealed that the prevalence of apolipoprotein B 100 (ApoB) and LDL-C levels 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 dyslipidemia. .ApoB is the main structural protein component of VLDL and LDL, allows the intercellular transport of cholesterol and triglycerides, which serve distinct roles in the body. .Our previous study suggested that functional TSH receptor (TSHR) is presented on hepatocyte membrane, through which TSH increases the liver VLDL-C secretion, and ultimately promotes the development of dyslipidemia. Additionally, our latest reports showed that compared with wild type (Tshr+/+) mice, Tshr-/- mice exhibit a relatively lower degree of ApoB expression. Whether TSH regulates hepatic VLDL-C secretion through ApoB 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) experiments and the relative key targets intervention approaches, we will elucidate the key molecules and major signaling networks about the effection of TSH on ApoB in the liver, explore the pathophysioligical mechanism of elevated VLDL-C level in thyroidal dysfunction situation and further provide newly theoretical evidence for its treatment strategy.

促甲状腺激素（TSH）在脂代谢中具有重要调控作用。本课题组在研究TSH通过SREBP1c增加肝脏甘油三酯含量时发现：TSH影响调控VLDL输出的关键基因ApoB的表达。VLDL输出是LDL升高的关键因素，是动脉粥样硬化和心血管疾病最重要的危险因素。临床资料证实TSH与血LDL-C和apoB水平明显正相关。课题组预实验发现；TSH通过肝脏TSH受体（TSHR）增加血浆和肝细胞ApoB的含量和表达。目前关于TSH调节肝脏ApoB合成及VLDL输出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VLDL输出的关键分子ApoB,应用体内动物（条件性敲除甲状腺或肝脏Tshr基因小鼠）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ApoB介导增加VLDL输出的分子机制，为揭示TSH在血脂紊乱发生发展中的作用提供新思路。

甲状腺功能异常常伴有血脂代谢紊乱，亚甲减是继发性血脂异常的常见原因之一。在血脂紊乱的多个因素中，血浆LDL-C 升高被认为是动脉粥样硬化和心血管疾病最重要的危险因素。LDL 的主要来源是VLDL。VLDL 由肝脏合成并输出到循环血液中，然后脂解成LDL。因此，VLDL 输出是LDL 升高的关键因素。本课题组在研究TSH通过SREBP1c增加肝脏甘油三酯含量时发现：TSH影响调控VLDL输出的关键基因apoB的表达。临床资料证实TSH与血LDL-C和apoB水平明显正相关。本课题研究发现；1）TSH通过肝脏TSH受体（TSHR）增加血浆和肝细胞apoB的含量和表达；2）TSH作用于肝细胞上的TSHR，通过PI3K/AKT/mTOR信号通路调控Sort1的表达及活性，进而影响肝脏ApoB的代谢，从而调控肝脏VLDL的输出；3）AKT、mTOR和Sort1等分子在此调控过程中居于核心地位和发挥关键作用。本项目以TSH为切入点，围绕调节肝脏VLDL输出的关键分子apoB，应用体内动物（条件性敲除甲状腺或肝脏Tshr基因小鼠）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，阐明了TSH通过肝脏TSHR和apoB介导增加VLDL输出的分子机制，在医学实践上提示人们在关注血脂水平同时，尚需重视调节TSH，降低（亚临床甲减人群）血脂紊乱的发病率，并为血脂紊乱提供新的治疗策略。