Nutritional and Hormonal Pathways for Reduction of ApoB-lipoproteins

描述（由申请人提供）：甲状腺激素可降低胆固醇，并被建议作为高胆固醇血症的激素和营养疗法。T3是甲状腺激素，是甲状腺核受体最活跃的配体。相比之下，食物中发现的一种甲状腺形式T2的代谢作用涉及非甲状腺受体的过程。与甲状腺抑制剂不同，我们发现T2有效降低LDL受体敲除小鼠的胆固醇。这为我们提供了一个系统来探索调节血浆载脂蛋白ob水平的非ldl受体途径。在Aim 1中，我们建议研究野生型和LDL受体敲除小鼠在T2处理下的脂蛋白动力学、基因和蛋白表达，并与T3进行比较。目的2将使用转基因小鼠来确定在甲状腺功能减退的情况下，加入T2和T3是否需要这些基因产物来降低胆固醇或增加胆固醇。实验的意义在于，我们的研究将定义一个非LDL受体依赖的胆固醇降低过程，可以说明一个治疗靶点，作为他汀类药物的补充，他汀类药物不耐受和纯合子LDL受体缺乏的患者。

DESCRIPTION (provided by applicant): Thyroid hormones reduce cholesterol and have been proposed to function as a hormonal and nutritional therapy for hypercholesterolemia. T3 is the thyroid hormone that is most active as a ligand for thyroid nuclear receptors. In contrast, the metabolic effects of T2, a form of thyroid found in foods, are involved non-thyroid receptor processes. Unlike thyromimetics, we have found that T2 effectively lowers cholesterol in LDL receptor knockout mice. This provides us with a system to explore non-LDL receptor pathways regulating plasma apoB levels. In Aim 1, we propose to study lipoprotein kinetics, gene and protein expression in wild type and LDL receptor knockout mice treated with T2, and for comparison T3. Aim 2 will use genetically modified mice to determine whether addition of T2 and T3 require these gene products to reduce cholesterol or for increased cholesterol in the setting of hypothyroidism. The significance of the experiments is that our studies will define a non-LDL receptor dependent process for cholesterol reduction that could illustrate a therapeutic target useful as an addition to statins, in statin intolerance, and in patients with homozygous LDL receptor deficiency.