Regulation of the ABCG5 ABCG8 Sterol Transporter

ABCG5 ABCG8 甾醇转运蛋白的调节

基本信息

批准号：
7881405
负责人：
Gregory A Graf
金额：
$ 34.83万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881405
关键词：
Address Adenovirus Vector Albumins B-Lymphocytes Bile Acids Bile fluid Biliary Brain Cardiovascular Diseases Cells Cholesterol Cholesterol Homeostasis Diabetes Mellitus Diamond Diet Dietary Cholesterol Endoplasmic Reticulum Enterocytes Exhibits Fatty acid glycerol esters Gall Bladder Diseases Hepatic Hepatobiliary Hepatocyte Hyperlipidemia In Vitro Insulin Insulin Resistance Intestines Leptin Lipids Liver Measures Messenger RNA Modeling Molecular Molecular Chaperones Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Phenotype Phytosterols Plants Plasma Play Proteins Pulmonary Surfactant-Associated Protein C Pump Regulation Resistance Risk Factors Role Shellfish Signal Pathway Signal Transduction Solid Source Sterols Stress Synapsins Testing Transgenes absorption basal insulin bile canaliculus structure biological adaptation to stress cardiovascular risk factor cholesterol absorption db/db mouse diabetic endoplasmic reticulum stress human FOXO1A protein in vivo insight insulin signaling leptin receptor lipid transport mouse model novel prevent promoter protein misfolding public health relevance receptor recombinase research study response small molecule

项目摘要

DESCRIPTION (provided by applicant): The purpose of this project is to determine the mechanisms by which leptin regulates the ABCG5 ABCG8 (G5G8) sterol transporter and influences cholesterol metabolism in obesity. Obesity and diabetes (diabesity) are associated with increased risk of cardiovascular and gallbladder disease, elevated plasma cholesterol levels, and a predilection for cholesterol synthesis rather than absorption. High-fat diets induce a virtually identical phenotype in mice. In contrast, mice that lack leptin (ob/ob) or its receptor (db/db) are hyperphagic, obese and diabetic, yet exhibit increased cholesterol absorption, reduced cholesterol synthesis, decreased biliary cholesterol, and resistance to cholethiasis. These observations suggest that in obesity the presence or absence of a functional leptin axis profoundly impacts cholesterol metabolism with respect to absorption, synthesis and hepatobiliary transport. The central hypothesis of this proposal is that hepatic leptin signaling maintains G5G8 and prevents reductions in hepatobiliary cholesterol transport by ER stress in diabesity. The Aims are to 1) determine the role of hepatic leptin receptors on G5G8 abundance, activity and cholesterol metabolism in vivo, 2) determine the role of ER stress on G5G8 abundance in vivo and 3) determine the molecular mechanisms for regulation of G5G8 abundance by leptin, ER stress and the ISR. Leptin receptors will be selectively deleted from liver and brain to assess the role of this signaling pathway on G5G8 and cholesterol metabolism in obesity. The effects of leptin, ER stress and their interaction on G5G8 abundance will be determined in vivo and in vitro. The completion of these Aims will test our central hypothesis and elucidate the mechanisms by which the leptin axis modulates G5G8 abundance, hepatobiliary lipid transport and cholesterol metabolism in diabesity. Understanding the impact of this novel pathway on cholesterol metabolism will add insight to the effects of obesity on risk factors fo cardiovascular disease. PUBLIC HEALTH RELEVANCE: The ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes the accumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is known concerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanisms that are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2 diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.

描述（由申请人提供）：该项目的目的是确定瘦素调节 ABCG5 ABCG8 (G5G8) 甾醇转运蛋白并影响肥胖症中胆固醇代谢的机制。肥胖和糖尿病与心血管和胆囊疾病的风险增加、血浆胆固醇水平升高以及胆固醇合成而非吸收的倾向有关。高脂肪饮食在小鼠中诱导出几乎相同的表型。相比之下，缺乏瘦素（ob/ob）或其受体（db/db）的小鼠食量过多、肥胖且患有糖尿病，但胆固醇吸收增加、胆固醇合成减少、胆汁胆固醇减少以及对胆石症具有抵抗力。这些观察结果表明，在肥胖症中，功能性瘦素轴的存在或缺失会深刻影响胆固醇代谢的吸收、合成和肝胆转运。该提议的中心假设是肝脏瘦素信号传导维持 G5G8 并防止糖尿病中 ER 应激导致的肝胆胆固醇转运减少。目的是 1) 确定肝瘦素受体对体内 G5G8 丰度、活性和胆固醇代谢的作用，2) 确定 ER 应激对体内 G5G8 丰度的作用，以及 3) 确定通过以下方式调节 G5G8 丰度的分子机制：瘦素、ER 应激和 ISR。瘦素受体将从肝脏和大脑中选择性删除，以评估该信号通路对肥胖中 G5G8 和胆固醇代谢的作用。瘦素、ER 应激及其相互作用对 G5G8 丰度的影响将在体内和体外测定。这些目标的完成将检验我们的中心假设，并阐明糖尿病中瘦素轴调节 G5G8 丰度、肝胆脂质转运和胆固醇代谢的机制。了解这一新途径对胆固醇代谢的影响将有助于了解肥胖对心血管疾病危险因素的影响。公共健康相关性：ABCG5 ABCG8 甾醇转运蛋白是身体抵抗膳食胆固醇和植物和贝类等来源的其他甾醇积累的主要机制。关于调节其丰度和活性的机制知之甚少。该提案解决了肥胖和 2 型糖尿病小鼠模型中导致 G5G8 丰度和活性降低的机制，以便深入了解导致肥胖中胆固醇积累的因素。