Regulation of the ABCG5 ABCG8 Sterol Transporter

项目描述（由申请人提供）：本项目旨在确定瘦素调节肥胖中ABCG5 ABCG8 （G5G8）固醇转运体并影响胆固醇代谢的机制。肥胖和糖尿病（糖尿病）与心血管和胆囊疾病风险增加、血浆胆固醇水平升高以及胆固醇合成倾向而非吸收倾向相关。高脂肪饮食在小鼠中诱导了几乎相同的表型。相反，缺乏瘦素（ob/ob）或其受体（db/db）的小鼠会贪食、肥胖和糖尿病，但表现出胆固醇吸收增加、胆固醇合成减少、胆胆固醇降低和对胆石症的抵抗。这些观察结果表明，在肥胖中，功能性瘦素轴的存在或缺失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，肝瘦素信号传导维持G5G8，并防止糖尿病内质网应激引起的肝胆胆固醇运输减少。目的：1)确定肝脏瘦素受体对体内G5G8丰度、活性和胆固醇代谢的影响；2)确定内质网应激对体内G5G8丰度的影响；3)确定瘦素、内质网应激和ISR调控G5G8丰度的分子机制。我们将从肝脏和大脑中选择性地删除瘦素受体，以评估该信号通路在肥胖中G5G8和胆固醇代谢中的作用。瘦素、内质网应激及其相互作用对G5G8丰度的影响将在体内和体外进行研究。这些目标的完成将验证我们的中心假设，并阐明瘦素轴调节糖尿病患者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。公共卫生相关性：ABCG5 ABCG8甾醇转运体是人体反对膳食胆固醇和其他来自植物和贝类的甾醇积累的主要机制。关于调节其丰度和活性的机制，人们知之甚少。本研究旨在探讨肥胖和2型糖尿病小鼠模型中G5G8丰度和活性降低的机制，从而深入了解导致肥胖中胆固醇积累的因素。

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.