高甘油三酯对甲状腺功能减退症的影响及机制

Hypothyroidism is a common disease, which has been found to be associated with genetic and environmental factors. However, its etiology has not been fully elucidated. Lipotoxicity induced by high-fat diet plays an important role in the occurrence of endocrine and metabolic diseases such as diabetes, but its impact on thyroid disease has never been explored. Our previous study found that hypertriglyceridemia can increase the risk of hypothyroidism by a large-scale epidemiological survey, we also found that in the rat fed with high-fat (lard) diet, the triglycerides and free fatty acid (FFA) deposited in the thyroid of, serum thyroid hormone (TT4) levels were significantly reduced, and free fatty acid levels were negatively correlated with TT4, which suggested that high-fat diet can induce the occurrence of hypothyroidism. Based on our previous study, our this research mainly focused on the effect of lipotoxicity induce by high triglyceride on the occurrence of hypothyroidism, using in vitro (FFA treated thyroid cells and interference, blocking or activate the expression of key molecules, etc.) and in vivo (high-fat diet, conditional knockout of thyroid gene, drug intervention and other animal models) experiments, we will demonstrated the effect of high triglyceride diet on thyroid function, elucidate the regulatory pathways and key molecular, clarify the patho-physiological changes that lipotoxicity induced hypothyroidism, which will reveal the pathogenesis of hypothyroidism and further provide newly evidence for its prevention and treatment strategies.

甲状腺功能减退（甲减）是一种常见病，与遗传和环境因素有关，病因尚未完全阐明。高脂饮食诱发的脂毒性在糖尿病等内分泌代谢疾病发生中具有重要作用，但对甲状腺的影响国内外未见报道。本课题组大规模流行病学调查发现，高甘油三酯血症增加甲减的患病风险；基础研究证实，高脂（猪油）喂养的大鼠甲状腺内甘油三酯、游离脂肪酸沉积，血清甲状腺激素（TT4）水平显著降低，且游离脂肪酸与TT4水平负相关，提示高脂饮食与甲减密切关联。本项目在此基础上将以高甘油三酯为切入点，围绕甲减，在分子、细胞和整体三个水平，应用多学科技术平台，采用体外（游离脂肪酸处理甲状腺细胞及干扰、阻断或激活关键分子表达等）和体内（高甘油三酯饮食、条件性甲状腺基因敲除、药物干预等动物模型）相结合的研究策略，明确高甘油三酯对甲状腺功能的影响及其调控途径和关键分子，阐明脂毒性引起甲减的病理生理变化，为揭示甲减的发病机制及制订防治策略提供新的依据和思路。

脂毒性是多种内分泌代谢性疾病的共同致病因素。甲状腺功能减退（甲减）影响广，危害大，患病率持续升高，明确其病因是临床亟待解决问题。项目组发现高甘油三酯饲料喂养动物甲状腺组织脂质饱和度增加，血清TSH升高，TT4、FT4显著下降，甲状腺摄碘能力明显降低，甲状腺组织形态结构异常，机体能量代谢下降，甲状腺激素生物合成关键分子甲状腺球蛋白、钠碘转运体和甲状腺过氧化物酶的表达及功能显著下调。进一步的机制研究发现，脂毒性一方面激活甲状腺滤泡上皮细胞内质网应激经典通路（PERK-eIF2α）并加快甲状腺球蛋白通过蛋白酶体途径的降解，另一方面诱导甲状腺亲环素D表达上调、诱导线粒体应激发生。亲环素D基因敲除可显著改善脂毒性引起的的血清TT4水平下降及甲状腺球蛋白表达减少。另外，线粒体蛋白琥珀酰化水平的下降也在高脂饮食诱导的甲状腺功能减退中发挥作用。饮食干预可明显改善高脂喂养引起的甲状腺球蛋白合成减少及甲状腺功能减低。本项目明确了甲状腺是脂毒性作用的靶器官，阐明了脂毒性导致甲状腺功能减退的关键环节和干预靶点，为早期防治甲状腺功能减退提供新的策略。