GENETICS & REGULATION OF HEPATIC LIPASE

该提案的长期目标是确定肝脂酶（HL）水平的调节机制，并确定HL基因位点的遗传变异如何在各种生理和病理状态下调节这些水平。HL通过催化甘油三酯和磷脂的水解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风险因素相关：血浆高密度脂蛋白胆固醇（HDL-C）浓度降低和小而致密的低密度脂蛋白（LDL）颗粒患病率增加。HL活性总变异性的显著比例（20-30%）由HL基因调控序列中的常见遗传变异解释，由此观察到变异形式与较低的HL和较高的HDL 2水平相关。性别是另一个调节因素，因为平均而言，女性的HDL 2水平较高，HL水平较低。该建议的基本假设是，首先，一种或多种观察到的调控序列变体导致HL基因表达减少，这反过来又导致HDL-C水平升高，并且表达受胆固醇和雌激素调节。我们的初步体外研究表明，甾醇类上调和雌激素下调HL基因启动子的活性，分别。具体目标是：1）通过关联和连锁分析确定观察到的LIPC启动子变体是否是肝脂肪酶活性和HDL 2雌激素和固醇水平的观察到的个体间差异的基础，并评估调节序列变体调节HL水平与性别、绝经状态、雌激素替代疗法和腹内脂肪沉积之间关系的作用。这些研究的结果将为HL活性和相关血浆脂蛋白谱的个体间变异的分子遗传基础提供见解。这将为靶向脂蛋白修饰的新药物方法打开大门。

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.