胆固醇超载诱发内质网应激对甲状腺功能的影响及机制

The phenomenon that cholesterol could trigger various diseases has been taken general attention. No research on thyroid dysfunction induced by cholesterol overloading has been reported. Our previous study has found that high-cholesterol feeding significantly decreased serum thyroid hormone levels, and down-regulated the expression of NIS, together with ER stress of thyroid follicular cells. However, the mechanism involved is unknown. Therefore, taking NIS as the starting point and using both in vivo (apoE and Bip gene knockout rat model) and in vitro (gene mutation, luciferase assay and CHIP) experiments, we will elucidate the key molecules and major signaling networks about the effect of cholesterol on NIS in the thyroid, further revealed a new pathogenesis mechanism for thyroid dysfunction. This study is a strong innovative research, will provide newly theoretical evidence for clinical prevention and treatment of thyroid disease.

胆固醇诱发心血管疾病以外多脏器病变的现象正在引起广泛关注，然而胆固醇超载对甲状腺功能的影响目前尚无报道。本课题组前期研究发现，高胆固醇饮食喂养显著降低大鼠血清甲状腺激素水平，下调甲状腺激素合成关键分子NIS表达，伴随内质网应激的发生，然而具体机制不明。本项目以甲状腺激素合成的关键分子NIS为切入点，应用体内实验（基因敲除、基因干扰等多种动物模型）与体外实验（基因突变质粒转染、荧光素酶报告基因、染色质免疫共沉淀等技术）相结合的方法，从整体、细胞及分子水平探讨①胆固醇超载对甲状腺功能的影响；②内质网应激在胆固醇超载致甲状腺功能异常中的作用和地位；③内质网应激介导NIS表达下调的调控位点。旨在阐明胆固醇通过诱导内质网应激减少甲状腺激素合成的作用及分子机制，为临床防治甲状腺疾病提供新的思路和策略。

甲状腺功能减退是全球性人口健康问题，与高胆固醇血症常伴发，具体机制不明。高胆固醇诱发的脂毒性是多种代谢性疾病的共同致病因素，然而对甲状腺功能的影响国内外未见报道。本项目在人群中发现高胆固醇血症是甲减发展的独立危险因素，提示甲状腺是胆固醇所致脂毒性的靶器官；在动物模型中发现胆固醇可异位沉积于甲状腺、诱发甲减，首次证实甲状腺是胆固醇超载所致脂毒性的靶器官；机制上证实胆固醇抑制甲状腺激素生物合成，内质网功能异常是胆固醇超载影响甲状腺激素生物合成障碍的中心环节，明确饮食干预及降脂干预明显逆转胆固醇过量摄入诱发的甲状腺减退。本项目优化了研究甲状腺结构和功能的技术方法，已申报多项国家发明专利。为临床防治甲状腺疾病提供新的思路和策略。