Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol.
Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol.
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DOI：
10.1210/mend.14.11.0548
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发表时间：
2000-11
影响因子：
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通讯作者：
H. Gullberg;M. Rudling;D. Forrest;B. Angelin;B. Vennström
中科院分区：
文献类型：
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作者：
H. Gullberg;M. Rudling;D. Forrest;B. Angelin;B. Vennström
甲状腺激素（T3）影响肝脏胆固醇代谢，并且先前的研究已经确定了该激素在胆固醇7 α-羟化酶（CYP 7A）（胆汁酸合成中的限速酶）的调节中的重要作用。为了评估甲状腺激素受体（TR）α 1和β在这一调节中的各自贡献，在甲状腺功能减退和甲状腺功能亢进条件下研究了TR α 1和TR β基因敲除小鼠对2%膳食胆固醇和T3的反应。我们的实验表明，T3对CYP 7A活性和mRNA水平的正常刺激在TRbeta-/-小鼠中丢失，但在TRalpha 1-/-小鼠中没有，确定TRbeta是T3对CYP 7A作用的介体，因此，是体内胆固醇代谢的主要调节剂。有些出乎意料的是，T3缺陷型TRbeta-/-小鼠在用膳食胆固醇攻击后显示出增强的CYP 7A应答，并且这些动物没有发展到野生型（wt）对照的程度的高胆固醇血症。后者的结果提供了强有力的支持的概念，TRs可以发挥调节作用，在体内独立的T3。
Thyroid hormone (T3) influences hepatic cholesterol metabolism, and previous studies have established an important role of this hormone in the regulation of cholesterol 7alpha-hydroxylase (CYP7A), the rate-limiting enzyme in the synthesis of bile acids. To evaluate the respective contribution of thyroid hormone receptors (TR) alpha1 and beta in this regulation, the responses to 2% dietary cholesterol and T3 were studied in TRalpha1 and TRbeta knockout mice under hypo- and hyperthyroid conditions. Our experiments show that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in TRbeta-/- but not in TRalpha1-/-mice, identifying TRbeta as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient TRbeta-/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent as did wild-type (wt) controls. The latter results lend strong support to the concept that TRs may exert regulatory effects in vivo independent of T3.