Regulation of the ABCG5 ABCG8 Sterol Transporter

ABCG5 ABCG8 甾醇转运蛋白的调节

• 批准号: 8072534
• 负责人: Gregory A Graf
• 金额: $ 31.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/8072534
• 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; Health; 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

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）：本项目的目的是确定瘦素调节ABCG 5 ABCG 8（G5 G8）固醇转运蛋白和影响肥胖症胆固醇代谢的机制。肥胖和糖尿病（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不是吸收的偏好有关。高脂饮食在小鼠中诱导几乎相同的表型。相比之下，缺乏瘦素（ob/ob）或其受体（db/db）的小鼠是贪食的、肥胖的和糖尿病的，但表现出胆固醇吸收增加、胆固醇合成减少、胆汁胆固醇减少和对胆固醇的抗性。这些观察结果表明，在肥胖症的存在或不存在的功能性瘦素轴深刻影响胆固醇代谢的吸收，合成和肝胆运输。该建议的中心假设是，肝脏瘦素信号维持G5 G8，并防止糖尿病患者ER应激导致肝胆胆固醇转运减少。目的是1）确定肝脏瘦素受体对体内G5 G8丰度、活性和胆固醇代谢的作用，2）确定ER应激对体内G5 G8丰度的作用，以及3）确定瘦素、ER应激和ISR调节G5 G8丰度的分子机制。将选择性地从肝脏和大脑中删除瘦素受体，以评估该信号通路在肥胖症中对G5 G8和胆固醇代谢的作用。将在体内和体外确定瘦素、ER应激及其相互作用对G5 G8丰度的影响。这些目标的完成将检验我们的中心假设，并阐明瘦素轴调节G5 G8丰度，肝胆脂质转运和胆固醇代谢在糖尿病中的机制。了解这种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。公共卫生关系：胆固醇转运蛋白ABCG 5 ABCG 8是人体抵抗来自植物和贝类等来源的膳食胆固醇和其他固醇积累的主要机制。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G5 G8丰度和活性降低的机制，以深入了解导致肥胖症中胆固醇积累的因素。