自身免疫性甲状腺炎脂代谢稳态失衡的同位素示踪研究

Lipid metabolism disorder has become a serious public health problem in China. The prevalence of autoimmune thyroiditis in China is much high, but our understanding of autoimmune thyroiditis is only the tip of the iceberg. In our previous SPECT-China study, a significant correlation and causal relationship between autoimmune thyroiditis and lipid metabolism disorder was found. Therefore, we hypothesized that autoimmune thyroiditis played a very important role on homeostasis of lipid metabolism，which was independent of TSH levels. However, its specific pathways and mechanisms are not yet clear. This project, based on biochemical mechanism, aims to evaluate the lipid metabolism homeostasis parameters (fat deposition, fat synthesis, lipolysis and fatty acid oxidation) by tracing dynamic changes of lipid metabolism in experimental autoimmune thyroiditis rats with the long-term and short-time isotope labeling techniques (1-14C-oleic acid, U-13C-glycerol and 9, 10-3 H-palmitic acid), analyze its specific biochemical pathways. Further, we will detect the key enzymes during the process of fat synthesis, lipolysis and fatty acid oxidation as well as the expression of inflammatory and lipid-related receptors for its molecular mechanisms.. This project could provide scientific proof for preventing lipid disorders in patients with autoimmune thyroiditis.

脂代谢紊乱是我国十分严峻的公共卫生问题。自身免疫性甲状腺炎在我国发病率高，而我们对该疾病的认识却只是冰山一角。本项目前期SPECT-China流行病学研究发现：自身免疫性甲状腺炎与脂代谢异常存在显著相关及因果关系。由此，我们推测自身免疫性甲状腺炎具有非依赖TSH水平与脂代谢紊乱相关机制的存在，但其具体通路和机制目前尚不清晰。本项目建立实验性自身免疫甲状腺炎大鼠模型，基于生化原理，采用同位素示踪标记化合物（1-14C-油酸、9,10-3H-棕榈酸和U-13C-甘油），利用同位素示踪平台评估脂代谢稳态参数（脂质沉积、脂肪合成、脂肪分解和脂肪酸氧化）变化，阐明自身免疫性甲状腺炎脂代谢稳态失衡具体生化通路改变。同时，对脂肪合成、分解及氧化过程中的关键酶及与炎症、脂代谢相关受体的表达进行检测，进一步明确自身免疫性甲状腺炎脂代谢紊乱的分子机制，为脂代谢异常及自身免疫性甲状腺炎的完善诊疗提供科学依据。

项目背景.脂代谢紊乱是我国十分严峻的公共卫生问题。自身免疫性甲状腺炎在我国发病率高，而我们对该疾病的认识却只是冰山一角，既往人群研究表明自身免疫性甲状腺炎与脂代谢异常可能相关。自身免疫性甲状腺炎与脂代谢之间是否存在关联及其具体机制目前尚不清晰。.主要研究内容.本项目建立实验性自身免疫甲状腺炎大鼠模型（EAT）（分为6组：普食/高脂对照组：NC/HC；普食/高脂EAT组：NE/HE；普食/高脂EAT加强组：NEI/HEI)，采用同位素示踪标记化合物（1-14C-油酸、9,10-3H-棕榈酸和U-13C-甘油），利用同位素示踪平台评估脂代谢稳态参数（脂质沉积、脂肪合成、脂肪分解和脂肪酸氧化）变化，并检测脂肪合成、分解及氧化过程中的关键酶及与脂代谢相关受体的表达。.结果.1.EAT及EAT加强组的TgAb水平显著高于对照组，表明建模成果。FT4、FT3、T4、T3在HC、HE及HEI组呈现显著增高趋势。.2.NC、NE及NEI组间体脂含量差异不显著；HEI组体脂含量、TG水平、体重、宫旁脂肪、肾周脂肪含量显著高于其余各组。.3.同位素示踪平台发现：EAT及EAT加强组脂肪沉积及合成率均不显著高于正常对照；脂肪分解方面，NE、NEI组脂肪分解多于NC组，高脂组中这种差异不明显。脂肪酸β氧化方面，NE组脂肪酸β氧化明显高于其他各组。.4.NE、NEI组较NC组，肝脏LDLR、LPL及MTTP表达上调。HEI组较HC组，MTTP表达上调。.科学意义.自身免疫甲状腺炎大鼠在普食喂养情况下，脂肪分解及脂肪酸β氧化增强，肝脏LDLR、LPL及MTTP表达上调。然而，在高脂高碘喂养下，体内脂肪含量、TG水平增加。本项目对单纯TgAb升高的自身免疫背景下的脂代谢稳态变化进行了探讨，对自身免疫对脂代谢的影响提供了理论基础，有望通过进一步研究，为脂代谢疾病的防治提供新的策略。