Genetics and Regulation of Hepatic Lipase

肝脂肪酶的遗传学和调控

• 批准号: 6542482
• 负责人: SAMIR Sami DEEB
• 金额: $ 34.11万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542482
• 关键词: clinical research; colestipol; coronary disorder; enzyme activity; estrogens; fatty acids; gel mobility shift assay; gender difference; gene expression; genetic polymorphism; genetic promoter element; genetic susceptibility; hepatic lipase; high density lipoproteins; human subject; human tissue; insulin sensitivity /resistance; linkage mapping; low density lipoprotein; polymerase chain reaction; protein binding; racial /ethnic difference; single strand conformation polymorphism; site directed mutagenesis; transcription factor; yeast two hybrid system

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.

描述（由申请人提供）：本提案的长期目标是确定人类肝脂肪酶（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危险因素相关：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）颗粒的增加。包括我们小组的研究在内的各种研究表明，HL活性变异的很大一部分（20-25%）是由HL基因调控序列的共同遗传变异来解释的，而种族/种族背景、性别和腹内脂肪积累是其他重要的调节因素。该建议的基本假设是：首先，HL基因的其他变异导致了不同民族/种族群体中HL活性和相关脂蛋白谱的变化。第二，肝脂肪酶活性高是心血管疾病发展的风险。第三，活性由配体调节的转录因子将成为药物设计的极好靶点。第四，HL活性是由常用的调节脂质的药物调节的。我们的初步结果支持这些假设。具体目标是：1)确定一小组遗传标记，以预测HL活性水平和相关脂蛋白表型。2)明确所有与心血管疾病风险相关的肝脂肪酶基因变异。3)鉴定并表征调节肝脂肪酶基因表达的转录因子。4)确定人类受试者脂质代谢紊乱和胰岛素抵抗对HL活性的影响。这些研究的结果将为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见解。调节HL活性的关键转录因子可作为新型药物诱导有利脂蛋白谱的靶点。遗传标记在预测心血管风险和治疗反应方面是有价值的。