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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：
8457007
负责人：
Ira J Goldberg
金额：
$ 19.04万
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/8457007
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.

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。