Endoplasmic Reticulum Stress May Play a Pivotal Role in Lipid Metabolic Disorders in a Novel Mouse Model of Subclinical Hypothyroidism.
Endoplasmic Reticulum Stress May Play a Pivotal Role in Lipid Metabolic Disorders in a Novel Mouse Model of Subclinical Hypothyroidism.
复制标题
内质网应激可能在亚临床甲状腺功能减退症新型小鼠模型的脂质代谢紊乱中发挥关键作用
DOI：
10.1038/srep31381
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发表时间：
2016-08-19
影响因子：
4.6
通讯作者：
Gao L
中科院分区：
文献类型：
--
作者：
Zhou L;Ding S;Li Y;Wang L;Chen W;Bo T;Wu K;Li C;Liu X;Zhao J;Xu C;Gao L
亚临床甲状腺功能减退症（subclinical hypothyroidism，SCH）由于其日益增加的患病率和潜在的有害影响，正成为一个全球性的健康问题。然而，SCH中脂质代谢紊乱的分子机制尚未完全阐明。此外，由于缺乏优化的小鼠模型，阐明SCH确切发病机制的进展受到阻碍。应用他巴唑（MMI）建立无创性SCH小鼠模型。8周龄C57 BL/6小鼠经饮水给予MMI。12周后，MMI处理的小鼠显示SCH的诊断标准：血清促甲状腺激素（TSH）水平升高，甲状腺激素水平恒定，持续约8周。值得注意的是，SCH小鼠表现出明显的脂质代谢紊乱，包括血脂异常和肝脏脂质蓄积。进一步分析表明，SCH小鼠或体外TSH升高诱导肝内质网应激（ER应激），可能通过IRE 1 α/XBP-1途径。有趣的是，当我们使用4-苯基丁酸抑制SCH小鼠的ER应激4周时，血脂异常和肝脏脂质积聚均显著减轻。我们的研究结果表明，一个优化的SCH小鼠模型，可以建立使用MMI和ER应激可能在SCH的脂质代谢异常中起着关键作用。
Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSHin vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.