Distinct Dysregulation of Lipid Metabolism by Unliganded Thyroid Hormone Receptor Isoforms
Distinct Dysregulation of Lipid Metabolism by Unliganded Thyroid Hormone Receptor Isoforms
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DOI：
10.1210/me.2008-0311
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发表时间：
2009-03-01
影响因子：
--
通讯作者：
Cheng, S. Y.
中科院分区：
文献类型：
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作者：
Araki, O.;Ying, H.;Cheng, S. Y.
甲状腺激素受体（TR）在能量稳态中发挥着关键作用。为了了解 TR 在体内脂质稳态中的作用，我们采用了功能丧失的方法，通过创建 TR α 基因（TR α 1PV 小鼠）或 TR α 基因（TR β PV 小鼠）有针对性突变的敲入突变小鼠。在甲状腺激素抵抗患者中发现的 PV 突变表现出强大的显性失活活性。在这里，我们表明，与 TR α 1PV 小鼠相比，TR β PV 小鼠的 WAT 没有显着降低，但血清游离脂肪酸和总甘油三酯显着增加。此外，TR beta PV小鼠的肝脏显着增大（33%），脂质积累过多，但TR alpha 1PV小鼠的肝脏质量减少（23%），脂质缺乏。这些结果表明apo-TR β 和apo-TR α 1 在脂质代谢中表现出明显的异常。进一步的生化分析表明，脂肪生成酶表达的增加、过氧化物酶体增殖物激活受体γ（Pparγ）信号的激活以及脂肪酸β氧化活性的降低导致了TR beta PV小鼠肝脏中的脂肪形成性脂肪变性和脂质积累。相反，TR α 1PV 小鼠肝脏中脂肪生成酶和 Ppar γ 的表达降低。这些结果表明，肝脏中 TR 对脂质代谢至关重要的基因的调节是异构体依赖性的。这些结果表明，apo-TR β 和 apo-TR α 1 对脂质代谢具有不同的影响，并且两种 TR 亚型都有助于甲状腺功能减退症脂质代谢的发病机制。 (分子内分泌学 23: 308-315, 2009)
Thyroid hormone receptors (TRs) play critical roles in energy homeostasis. To understand the role of TRs in lipid homeostasis in vivo, we adopted the loss-of-function approach by creating knock-in mutant mice with targeted mutation in the TR alpha gene (TR alpha 1PV mouse) or TR alpha gene (TR beta PV mouse). The PV mutation, identified in a patient with resistance to thyroid hormone, exhibits potent dominant-negative activity. Here we show that in contrast to TR alpha 1PV mouse, TR beta PV mice exhibited no significant reduction in WAT but had significant increases in serum free fatty acids and total triglycerides. Moreover, the liver of TR beta PV mice was markedly increased (33%) with excess lipid accumulation, but the liver mass of TR alpha 1PV mouse was decreased (23%) with paucity of lipids. These results indicate that apo-TR beta and apo-TR alpha 1 exerted distinct abnormalities in lipid metabolism. Further biochemical analyses indicate that increased lipogenic enzyme expression, activated peroxisome proliferator-activated receptor gamma(Ppar gamma) signaling, and decreased fatty acid beta-oxidation activity contributed to the adipogenic steatosis and lipid accumulation in the liver of TR beta PV mice. In contrast, the expression of lipogenic enzymes and Ppar gamma was decreased in the liver of TR alpha 1PV mice. These results suggest that the regulation of genes critical for lipid metabolism by TRs in the liver is isoform dependent. These results indicate that apo-TR beta and apo-TR alpha 1 had different effects on lipid metabolism and that both TR isoforms contribute to the pathogenesis of lipid metabolism in hypothyroidism. (Molecular Endocrinology 23: 308-315, 2009)