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：
8274829
负责人：
Gregory A Graf
金额：
$ 31.12万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274829
关键词：
Acids Address Adenovirus Vector Albumins B-Lymphocytes Bile Acids Bile fluid Biliary Brain Cardiovascular Diseases Cells Cholesterol Cholesterol Homeostasis Diabetes Mellitus Diamond Diet Dietary Cholesterol 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 Synapsins Testing Transgenes absorption basal insulin bile canaliculus structure biological adaptation to stress cardiovascular disorder risk 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 receptor recombinase research study response small molecule

项目摘要

6. Project Summary 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 for cardiovascular disease.

六、项目概要该项目的目的是确定瘦素调节 ABCG5 ABCG8 的机制 (G5G8) 甾醇转运蛋白并影响肥胖中的胆固醇代谢。肥胖和糖尿病（糖尿病）与心血管和胆囊疾病的风险增加有关，血浆胆固醇水平升高，并且倾向于合成胆固醇而不是吸收。高脂肪饮食在小鼠中诱导出几乎相同的表型。相反，缺乏瘦素（ob/ob）或其受体的小鼠 (db/db) 是贪食者、肥胖者和糖尿病患者，但表现出胆固醇吸收增加、胆固醇降低合成、降低胆汁胆固醇和抵抗胆石症。这些观察结果表明，在肥胖功能性瘦素轴的存在或缺失深刻影响胆固醇代谢吸收、合成和肝胆转运。该提案的中心假设是肝脏瘦素信号维持 G5G8 并防止减少糖尿病中 ER 应激导致的肝胆胆固醇转运。目标是 1) 确定角色肝脏瘦素受体对G5G8丰度、活性及体内胆固醇代谢的决定作用 ER应激对体内G5G8丰度的影响以及3)确定G5G8调节的分子机制瘦素、ER 应激和 ISR 的丰度。瘦素受体将被选择性地从肝脏和大脑中删除评估该信号通路对肥胖中 G5G8 和胆固醇代谢的作用。瘦素的作用， ER 应激及其对 G5G8 丰度的相互作用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瘦素的机制轴调节糖尿病中的 G5G8 丰度、肝胆脂质转运和胆固醇代谢。了解这一新途径对胆固醇代谢的影响将有助于深入了解以下因素的影响：肥胖与心血管疾病的危险因素有关。