Genetics and Regulation of Hepatic Lipase

描述(由申请人提供)：这项建议的长期目标是确定人类肝脏脂肪酶(HL)水平的调节机制，并确定在各种生理和病理状态下，HL基因位点的遗传变异如何调节这些水平。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危险因素有关：血浆高密度脂蛋白胆固醇(HDLC)浓度降低和小而致密的低密度脂蛋白(LDL)颗粒增加。各种研究，包括我们小组的研究表明，很大比例(20%-25%)的HL活性变异是由HL基因调控序列中的共同遗传变异解释的，民族/种族背景、性别和腹内脂肪积累是其他重要的调节因素。这一建议的基本假设是：第一，HL基因的额外变异是不同民族/种族群体中HL活性和相关脂蛋白谱差异的原因。其次，高肝脂酶活性是心血管疾病发展的风险。第三，其活性受配体调节的转录因子将是药物设计的极佳靶点。第四，HL的活性受到调节血脂的常用药物的调节。我们的初步结果支持这些假设。其具体目的是：1)识别一组可以预测HL活性水平和相关脂蛋白表型的遗传标记。2)确定所有与心血管疾病风险相关的肝脂酶基因变异。3)鉴定和鉴定调节肝脂酶基因表达的转录因子。4)测定受试者脂代谢紊乱和胰岛素抵抗对HL活性的影响。这些研究的结果将对HL活性个体间差异的代谢和分子基础以及相关的血浆脂蛋白谱提供深入的了解。调节HL活性的关键转录因子可以作为诱导有利脂蛋白谱的新药的靶点。遗传标记在预测心血管风险和治疗反应方面将是有价值的。

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to define mechanisms of regulation of hepatic lipase (HL) levels in humans 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 (HDLC) and an increased prevalence of small, dense low density lipoprotein (LDL) particles. Various studies, including those of our group, have shown that a significant proportion (20-25%) of the variability in HL activity is explained by a common genetic variation in the regulatory sequences of the HL gene, and that ethnic/racial background, gender and intraabdominal fat accumulation are other important modulating factors. The underlying hypotheses of this proposal are: first, that additional variants in the HL gene are responsible for variation in HL activity and the associated lipoprotein profiles in different ethnic/racial groups. Second, that high hepatic lipase activity is a risk for the development of cardiovascular disease. Third, that transcription factors whose activity is modulated by ligands would be excellent targets for drug design. Fourth, that HL activity is modulated by the commonly used drugs that modulated lipids. Our preliminary results support these hypotheses. The specific aims are to: 1) Identify a small set of genetic markers that would predict levels of HL activity and the associated lipoprotein phenotypes. 2) Define all hepatic lipase gene variants that are associated with risk for cardiovascular disease. 3) Identify and characterize transcription factors that regulate hepatic lipase gene expression. 4) Determine in human subjects the impact of perturbation of lipid metabolism and insulin resistance on HL activity. The results of these studies will provide insights into the metabolic and molecular bases of interindividual variation in HL activity and the associated plasma lipoprotein profiles. Key transcription factors that regulate HL activity could serve as targets for novel pharmaceutical for inducing a favorable lipoprotein profile. The genetic markers would be valuable in predicting cardiovascular risk as well as response to therapy.