GENETICS & REGULATION OF HEPATIC LIPASE

遗传学

• 批准号: 2884900
• 负责人: SAMIR Sami DEEB
• 金额: $ 29.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2884900
• 关键词: colestipol; enzyme activity; estrogens; fatty acids; gel mobility shift assay; gender difference; gene expression; genetic polymorphism; genetic promoter element; genetic regulation; hepatic lipase; high density lipoproteins; hormone regulation /control mechanism; human tissue; insulin sensitivity /resistance; low density lipoprotein; messenger RNA; nucleoproteins; pharmacogenetics; polymerase chain reaction; protein binding; racial /ethnic difference; single strand conformation polymorphism; site directed mutagenesis; sterols

The long-term goals of this proposal are to define mechanisms of regulation of hepatic lipase (HL) levels and to determine how genetic variation at the HL gene locus modulates these levels under a variety of physiological and pathological states. HL plays a key role in lipoprotein metabolism by catalyzing the hydrolysis of triglycerides and phospholipids. A high level of HL is associated with two important metabolic risk factors for atherosclerosis: diminished concentrations of plasma high density lipoprotein cholesterol (HDL-C) and an increased prevalence of small, dense low density lipoprotein (LDL) particles. A significant proportion (20-30%) of the total variability in HL activity is explained by the common genetic variation in the regulatory sequences of the HL gene whereby, the variant form was observed to be associated with lower HL and higher HDL2 levels. Gender is another modulating factor since women have, on average, higher levels of HDL2 and lower levels of HL. The underlying hypotheses of this proposal are, first, that one or more of the observed regulatory sequence variants causes diminished HL gene expression which, in turn, results in increased HDL-C levels and expression is regulated by cholesterol and estrogens. Our preliminary in vitro studies indicate that sterols up-regulate and estrogens down-regulate activity of the HL gene promoter, respectively. The specific aims are to: 1) Determine by association and linkage analysis whether the observed LIPC promoter variants underlie the observed interindividual variation in levels of hepatic lipase activity and HDL2 estrogens and sterols and assess the role of the regulatory sequence variants modulate the relationships between HL levels and gender, menopause status, estrogen replacement therapy and intra-abdominal fat deposits. The results of these studies will provide insights into the molecular genetic bases for interindividual variation in HL activity and the associated plasma lipoprotein profiles. This will open the door for novel pharmaceutical approaches that target modification of the lipoproteins.

该提案的长期目标是定义肝脂肪酶（HL）水平调节的机制，并确定HL基因基因座的遗传变异如何在各种生理和病理状态下调节这些水平。通过催化甘油三酸酯和磷脂的水解，HL在脂蛋白代谢中起关键作用。高水平的HL与动脉粥样硬化的两个重要代谢危险因素有关：血浆高密度脂蛋白胆固醇（HDL-C）的浓度降低，并且小，密集的低密度脂蛋白（LDL）颗粒的患病率增加。 HL活性总变异性的显着比例（20-30％）是由HL基因的调节序列的常见遗传变异解释的，因此观察到变体形式与HL和较高的HDL2水平相关。性别是另一个调节因素，因为女性平均HDL2水平较高和HL水平较低。该提案的基本假设首先是，一个或多个观察到的调节序列变体导致HL基因表达降低，而HL基因表达又导致HDL-C水平升高和表达受到胆固醇和雌激素的调节。我们的初步体外研究表明，固醇分别将HL基因启动子的活性下调和雌激素下调。具体目的是：1）通过关联和连锁分析确定观察到的LIPC启动子变体是否是观察到的肝脂肪酶活性和HDL2雌激素水平的个人间变化和固醇的个人间个体变化，并评估调节序列序列变异的作用，调节HL水平和性别水平和性别水平和性别替代的替代品之间的关系。这些研究的结果将为HL活性和相关的血浆脂蛋白谱的个体变异提供有关分子遗传碱基的见解。这将为靶向脂蛋白修饰的新型药物方法打开大门。