Nutritional and Hormonal Pathways for Reduction of ApoB-lipoproteins

减少 ApoB 脂蛋白的营养和激素途径

基本信息

批准号：
8302652
负责人：
Ira J Goldberg
金额：
$ 24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302652
关键词：
Affect Animals Apolipoproteins B Bile fluid Biliary Biochemistry Biology Blood Circulation Catabolism Chemistry Cholesterol Chylomicrons Clinical Clinical Research Data Diet Dose Employee Strikes Excision Familial Hypercholesterolemia Fatty acid glycerol esters Food Gene Expression Gene Proteins Goals Gray unit of radiation dose Guidelines Hepatic Hepatocyte Hormonal Hypothyroidism Intestines Italy Kinetics Knock-out Knockout Mice LDL Cholesterol Lipoproteins Ligands Lipase Lipids Lipoprotein Receptor Lipoproteins Liver Liver diseases Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolic Metabolism Modality Mus Mutation Nuclear Nuclear Receptors Nutritional Nutritional Support Oregon Pathway interactions Patients Pharmaceutical Preparations Physiological Plasma Printing Process Production Proteins Proteoglycan Proteomics Public Health Regulation Research Research Personnel Staging System Text Thyroid Gland Thyroid Hormones Thyronines Thyroxine United States Up-Regulation Very low density lipoprotein Wild Type Mouse apolipoprotein B-48 diabetes mellitus genetics dietary supplements experience feeding forest hormone therapy hypercholesterolemia lipid disorder lipid metabolism non-alcoholic fatty liver novel protein expression receptor research study therapeutic target therapy development thyronamine thyronine tool uptake

项目摘要

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.

描述（由申请人提供）：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 是甲状腺激素，作为甲状腺核受体的配体最活跃。相比之下，T2（食物中的一种甲状腺形式）的代谢作用涉及非甲状腺受体过程。与拟甲状腺素不同，我们发现 T2 可以有效降低 LDL 受体敲除小鼠的胆固醇。这为我们提供了一个探索调节血浆 apoB 水平的非 LDL 受体途径的系统。在目标 1 中，我们建议研究用 T2 治疗的野生型和 LDL 受体敲除小鼠的脂蛋白动力学、基因和蛋白质表达，并与 T3 进行比较。目标 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种非 LDL 受体依赖性降低胆固醇的过程，该过程可以说明作为他汀类药物的补充、他汀类药物不耐受以及纯合 LDL 受体缺陷患者的治疗靶点。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。尽管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的情况，并且对于 LDL 受体突变纯合子的患者无效。我们建议使用 T2（食物中发现的一种甲状腺激素）作为工具来研究它如何在缺乏 LDL 受体的情况下降低血浆胆固醇水平。我们的研究将定义一种非 LDL 受体依赖性降低胆固醇的过程，这可以说明替代他汀类药物治疗的治疗目标。