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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability
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Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

机译：选择性甲状腺激素受体-β活化：减轻体重，胆固醇和脂蛋白的策略（a）减少心血管疾病

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摘要

Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRβ activation on metabolic rate and HR with either TRα_1~(-/-) mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys. 3,5,3′-triiodi-L-thyronine (T_3) had a greater effect on increasing HR in WT than in TRα~(-/-) mice (ED_(15) values of 34 and 469 nmol/kg/day, respectively). T_3 increased metabolic rate [whole body oxygen consumption (MV_(O_2))] in both WT and TRα~(-/-) mice, but the effect in the TRα_1~(-/-) mice at the highest dose was half that of the WT mice. Thus, stimulation of MV_(O_2) is likely due to both TRα and -β. T_3 had equivalent potency for cholesterol reduction in WT and TRα~(-/-) mice. KB-141 increased MV_(O_2) with selectivities of 16.5-and 11.2-fold vs. HR in WT and TRα_1~(-/-) mice, respectively. KB-141 also increased MV_(O_2) with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).
机译：肥胖的治疗方法很少，尽管有针对高脂血症的有效治疗方法，但仍需要进一步的改进。甲状腺激素受体（TRs）调节体重和胆固醇水平。但是，甲状腺激素也具有有害作用，特别是对心脏。 TRβ亚型与降低胆固醇和可能提高代谢率有关，而TRα对于控制心率（HR）似乎更为重要。在目前的研究中，我们研究了TRβ_1激活对TRα_1〜（-/-）小鼠或选择性TRβ激动剂KB-141在小鼠，大鼠和猴子中的代谢率和HR的影响。 3,5,3'-triiodi-L-thyronine（T_3）对WT中的HR增加的影响大于TRα〜（-/-）小鼠（ED_（15）值为34和469 nmol / kg / day，分别）。 T_3在WT和TRα〜（-/-）小鼠中均增加了代谢率[全身耗氧量（MV_（O_2））]，但在最高剂量时对TRα_1〜（-/-）小鼠的影响是其的一半。 WT小鼠。因此，可能由于TRα和-β共同刺激了MV_（O_2）。 T_3具有等效的降低WT和TRα〜（-/-）小鼠胆固醇的能力。在WT和TRα_1〜（-/-）小鼠中，KB-141相对于HR分别具有16.5和11.2倍的选择性，从而增加了MV_（O_2）。在大鼠中，KB-141与HR相比，MV_（O_2）的选择性也高10倍，胆固醇降低了27倍。在灵长类动物中，KB-141引起显着的胆固醇，脂蛋白（a）和体重降低（1周后最多降低7％），而对HR无影响。 TRβ选择性激动剂可能是治疗肥胖，高胆固醇血症和脂蛋白升高（a）的一类以前尚未表征的药物。

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