Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):408-13. doi: 10.1097/MED.0b013e32833d6d46.
Thyroid hormone (3,3',5-triiodo-L-thyronine) plays an important role in thermogenesis and maintenance of lipid homeostasis. The present article reviews the evidence that 3,3',5-triiodo-L-thyronine regulates lipid metabolism via thyroid hormone receptors, focusing particularly on in-vivo findings using genetically engineered mice.
That lipid metabolism is regulated via thyroid hormone receptor isoforms in a tissue-dependent manner was recently uncovered by using knockin mutant mice harboring an identical mutation in the Thra gene (Thra1(PV) mouse) or the Thrb gene (Thrb(PV) mouse). The mutation in the Thra gene dramatically decreases the mass of both white adipose tissue and liver. In contrast, the mutation in the Thrb gene markedly increases the mass of liver with an excess depot of lipids, but no significant abnormality is observed in white adipose tissue. Molecular studies show that the expression of lipogenic genes is decreased in white adipose tissue of Thra1(PV) mice, but not in Thrb(PV) mice. Markedly increased lipogenic enzyme expression, and decreased fatty acid beta-oxidation activity contribute to the adipogenic steatosis and lipid accumulation in the liver of Thrb(PV) mice. In contrast, reduced expression of genes critical for lipogenesis mediates decreased liver mass with lipid scarcity in Thra1(PV) mice.
Studies using Thra1(PV) and Thrb(PV) mice indicate that apo-thyroid hormone receptor-beta and apo-thyroid hormone receptor-alpha-1 mediate distinct deleterious effects on lipid metabolism. Thus, both thyroid hormone receptor isoforms contribute to the pathogenesis of lipid abnormalities in hypothyroidism, but in a target tissue-dependent manner. These studies suggest that thyroid hormone receptor isoform-specific ligands could be designed as therapeutic targets for lipid abnormalities.
甲状腺激素（3,3',5-三碘-L-甲状腺原氨酸）在产热和维持脂质稳态中发挥重要作用。本文综述了甲状腺激素受体调节脂质代谢的证据，重点关注使用基因工程小鼠的体内发现。
使用携带 Thra 基因（Thra1(PV) 小鼠）或 Thrb 基因（Thrb(PV) 小鼠）中相同突变的基因敲入突变小鼠，最近发现脂质代谢通过甲状腺激素受体亚型以组织依赖的方式进行调节。Thra 基因的突变显著降低了白色脂肪组织和肝脏的质量。相比之下，Thrb 基因的突变使肝脏质量显著增加，脂肪堆积过多，但白色脂肪组织没有明显异常。分子研究表明，Thra1(PV) 小鼠白色脂肪组织中脂肪生成基因的表达减少，但 Thrb(PV) 小鼠则不然。显著增加的脂肪生成酶表达和减少的脂肪酸β氧化活性导致 Thrb(PV) 小鼠肝脏的脂肪生成性脂肪变性和脂质积累。相反，Thra1(PV) 小鼠中与脂肪生成关键的基因表达减少介导了肝脏质量减少和脂质缺乏。
使用 Thra1(PV) 和 Thrb(PV) 小鼠的研究表明，脱辅基甲状腺激素受体-β和脱辅基甲状腺激素受体-α-1对脂质代谢有不同的有害影响。因此，两种甲状腺激素受体亚型都有助于甲状腺功能减退症中脂质异常的发病机制，但以组织依赖的方式。这些研究表明，甲状腺激素受体亚型特异性配体可被设计为治疗脂质异常的靶点。
