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，已被提议用作高胆固醇血症的激素和营养疗法。作为甲状腺核受体的配体，T3是最活跃的甲状腺激素。相比之下，T2的代谢效应涉及非甲状腺受体过程，T2是食物中发现的一种甲状腺。与甲状腺类似物不同，我们发现T2有效地降低了低密度脂蛋白受体基因敲除小鼠的胆固醇。这为我们探索调节血浆载脂蛋白B水平的非低密度脂蛋白受体途径提供了一个系统。在目标1中，我们建议研究T2处理的野生型和低密度脂蛋白受体基因敲除小鼠的脂蛋白动力学、基因和蛋白表达，并与T3进行比较。AIM 2将使用转基因小鼠来确定添加T2和T3是否需要这些基因产物来降低胆固醇或在甲状腺功能减退的情况下增加胆固醇。实验的意义在于，我们的研究将定义一个非低密度脂蛋白受体依赖的降低胆固醇的过程，这可能说明一个治疗靶点，可用作他汀类药物的补充，用于他汀类药物不耐受和纯合子低密度脂蛋白受体缺陷患者。

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.