Congenital hypothryrodism and male rat liver: control vs congenital hypothryoidism

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology but its specific influence in liver is less understood. Here we studied how CH influences liver gene expression program in adulthood. Pregnant rats were given anti-thyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as a reduction in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, feed efficiency increased in CH and this was accompanied by significant catch-up growth. On PND80, significant reduction in body mass, tail length, and circulating IGF-I remained in CH rats. On the other hand, mRNA levels of known GH targeted genes were significantly up-regulated. Serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in expression for hepatic genes involved in lipid metabolism with an increased transcription of PPAR and reduced expression of genes involved in fatty acids and cholesterol uptake, cellular sterol efflux, triglycerides assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to hypothyroidism onset in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters, and to T3 replacement with enhanced activation of lipogenic transcriptional program. In summary, we provided in vivo evidence that neonatal hypothyroidism causes long-lasting effects on hepatic transcriptional program and tissue sensitivity to hormone treatment. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.甲状腺激素（Thyroid hormones）是哺乳动物正常生长发育所必需的物质。先天性新生儿甲状腺功能减退症（Congenital-neonatal hypothyroidism, CH）会对机体生理状态产生显著影响，但目前学界对其在肝脏中的具体作用机制仍不甚明确。本研究旨在探讨CH对成年个体肝脏基因表达程序的影响。本研究通过从妊娠第12天（GD12）至出生后第30天（PND30）向孕鼠投喂抗甲状腺药物他巴唑（甲巯咪唑，MMI），成功在雄性子代中构建CH模型。CH诱导的生长缺陷在出生后第二周即可通过体重与尾长的显著降低得以体现。停止MMI给药后，CH模型大鼠的饲料利用率显著提升，并伴随明显的追赶生长现象。在出生后第80天（PND80），CH模型大鼠仍表现出体重、尾长以及循环胰岛素样生长因子-I（IGF-I）水平的显著降低。与此同时，已知的生长激素（GH）靶基因的信使核糖核酸（mRNA）表达水平显著上调。血清甲状腺激素、胆固醇及甘油三酯水平未出现显著差异。与之相反，CH模型大鼠肝脏中参与脂质代谢的基因表达发生显著改变：过氧化物酶体增殖物激活受体（PPAR）的转录水平上调，而参与脂肪酸与胆固醇摄取、细胞甾醇外流、甘油三酯组装、胆汁酸合成及脂肪生成的基因表达则显著下调。上述基因表达改变与肝内脂质含量降低密切相关。最后，CH模型大鼠在成年后出现甲状腺功能减退时，血清脂肪酸与肝内胆固醇酯水平降低；而给予三碘甲状腺原氨酸（T3）替代治疗后，其脂肪生成相关转录程序的激活程度显著增强。综上，本研究通过体内实验证实，新生儿期甲状腺功能减退会对肝脏转录程序以及组织对激素治疗的敏感性产生长期影响。该结果凸显了发育阶段甲状腺功能正常状态对成年后肝脏正常生理功能的关键调控作用。