Regulation of the ABCG5 ABCG8 Sterol Transporter

ABCG5 ABCG8 甾醇转运蛋白的调节

• 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
• 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

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.

6.项目摘要 该项目的目的是确定瘦素调节ABCG 5 ABCG 8的机制 （G5 G8）固醇转运蛋白，并影响肥胖症的胆固醇代谢。 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， 升高的血浆胆固醇水平，以及胆固醇合成而不是吸收的偏好。高脂肪 饮食在小鼠中诱导几乎相同的表型。相反，缺乏瘦素（ob/ob）或其受体的小鼠， (db/db）是贪食的、肥胖的和糖尿病的，但表现出增加的胆固醇吸收，降低的胆固醇 胆固醇合成、降低胆固醇和抗胆固醇。这些观察表明，在 肥胖功能性瘦素轴的存在或缺乏深刻地影响胆固醇代谢， 在吸收、合成和肝胆转运方面。 该提议的中心假设是肝脏瘦素信号传导维持G5 G8并防止减少 在糖尿病患者ER应激肝胆胆固醇转运中作用。目标是：1）确定 肝脏瘦素受体对G5 G8丰度、活性和体内胆固醇代谢的影响; 2）确定作用 ER应激对体内G5 G8丰度的影响; 3）确定G5 G8调控的分子机制 通过瘦素、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， 评估该信号通路在肥胖症中对G5 G8和胆固醇代谢的作用。瘦素的作用， 将在体内和体外确定ER应激及其对G5 G8丰度的相互作用。 这些目标的完成将检验我们的中心假设，并阐明瘦素的作用机制。 轴调节G5 G8丰度，肝胆脂质转运和胆固醇代谢的糖尿病。 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。