Nutritional and Hormonal Pathways for Reduction of ApoB-lipoproteins

描述（由申请方提供）：甲状腺激素可降低胆固醇，并已被提议用作高胆固醇血症的激素和营养疗法。T3是作为甲状腺核受体的配体最活跃的甲状腺激素。相比之下，T2的代谢效应，一种在食物中发现的甲状腺形式，涉及非甲状腺受体过程。与拟甲状腺药物不同，我们发现T2能有效降低LDL受体敲除小鼠的胆固醇。这为我们探索非LDL受体途径调节血浆apoB水平提供了一个系统。在目的1中，我们建议研究T2处理的野生型和LDL受体敲除小鼠的脂蛋白动力学、基因和蛋白表达，并进行比较T3。目标2将使用转基因小鼠来确定是否T2和T3的添加需要这些基因产物来降低胆固醇或在甲状腺功能减退症的情况下增加胆固醇。这些实验的意义在于，我们的研究将定义一个非LDL受体依赖性的胆固醇降低过程，可以说明一个治疗靶点，可作为他汀类药物的补充，用于他汀类药物不耐受和纯合型LDL受体缺乏症患者。 公共卫生相关性：高血浆胆固醇水平是美国一个重要的公共卫生问题。虽然他汀类药物是一种有效的降胆固醇药物，但约1-5%的患者会出现他汀类药物不耐受，并且在LDL受体突变纯合子患者中无效。我们建议使用T2，一种在食物中发现的甲状腺激素形式，作为一种工具来研究它如何在没有LDL受体的情况下降低血浆胆固醇水平。我们的研究将确定一个非LDL受体依赖性的胆固醇降低过程，可以说明一个替代他汀类药物治疗的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: High plasma cholesterol level is an important public health problem in the United States. Although statin is an effective cholesterol-lowering drug, about 1-5% of patients experience statin intolerance and it is ineffective in patients homozygous for mutations in LDL receptors. We propose to use T2, a form of thyroid hormones found in foods, as a tool to study how it lowers plasma cholesterol levels in the absence of LDL receptor. Our studies will define a non- LDL receptor dependent process for cholesterol reduction that could illustrate a therapeutic target alternative to statin therapy.