Requirement for thyroid hormone receptor β in T3 regulation of cholesterol metabolism in mice
Requirement for thyroid hormone receptor β in T3 regulation of cholesterol metabolism in mice
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DOI：
10.1210/me.2002-0009
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发表时间：
2002-08-01
影响因子：
--
通讯作者：
Vennström, B
中科院分区：
文献类型：
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作者：
Gullberg, H;Rudling, M;Vennström, B
T-3通过核甲状腺激素受体β（TRbeta）（啮齿动物肝脏中最丰富的TR亚型）有效影响胆固醇代谢。在这里，我们已经测试了TRalpha 1，当其正常基因座表达水平增加时，是否可以取代TRbeta调节胆固醇代谢。通过使用过表达肝TR α 1 6倍的TR α 2-/-β-/-动物，实现了T-3结合受体总量的接近正常化。这些小鼠与TRbeta-/-和TRalpha 1-/-beta-/-小鼠相似，因为它们不能正确调节胆固醇7 α-羟化酶的表达，并且它们的血清胆固醇水平不受T-3的影响。因此，肝脏中TRalpha 1的过度表达不能替代TRbeta的缺失，这表明TRbeta基因在小鼠胆固醇代谢的T-3调节中具有独特的作用。然而，对T-3调节肝脏靶基因的研究表明，对TR β的依赖性并不普遍：T-3对I型碘甲腺原氨酸脱碘酶和低密度脂蛋白受体的调节部分被TR α 1过表达所挽救。这些体内数据表明，TRbeta对于T-3对胆固醇代谢的影响是必需的。TRalpha 1仅在某些情况下可以取代TRbeta，表明T-3对肝脏中生理和分子过程的调节以同种型特异性方式发生。
T-3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor beta (TRbeta), the most abundant TR isoform in rodent liver. Here, we have tested if TRalpha1, when expressed at increased levels from its normal locus, can replace TRbeta in regulation of cholesterol metabolism. By the use of TRalpha2-/-beta-/- animals that overexpress hepatic TRalpha1 6-fold, a near normalization of the total amount of T-3 binding receptors was achieved. These mice are similar to TRbeta-/- and TRalpha1-/-beta-/- mice in that they fail to regulate cholesterol 7alpha-hydroxylase expression properly, and that their serum cholesterol levels are unaffected by T-3. Thus, hepatic overexpression of TRalpha1 cannot substitute for absence of TRbeta, suggesting that the TRbeta gene has a unique role in T-3 regulation of cholesterol metabolism in mice. However, examination of T-3 regulation of hepatic target genes revealed that dependence on TRbeta is not general: T-3 regulation of type I iodothyronine deiodinase and the low density lipoprotein receptor were partially rescued by TRalpha1 overexpression. These in vivo data show that TRbeta is necessary for the effects of T-3 on cholesterol metabolism. That TRalpha1 only in some instances can substitute for TRbeta indicates that T-3 regulation of physiological and molecular processes in the liver occurs in an isoform-specific fashion.