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）：该提案的长期目标是定义人类中肝脂肪酶（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多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（HDLC）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。各种研究，包括我们小组的研究，都表明，HL活性变异性的显着比例（20-25％）是由HL基因的调节序列的常见遗传变异来解释的，并且种族/种族背景，性别和腹部脂肪积累是其他重要的调节因素。该提案的基本假设是：首先，HL基因中的其他变体负责HL活性的变化以及不同种族/种族群体中相关的脂蛋白谱。其次，高肝脂肪酶活性是发生心血管疾病的风险。第三，其活性由配体调节的转录因子将是药物设计的绝佳靶标。第四，HL活性是由调节脂质的常用药物调节的。我们的初步结果支持这些假设。具体目的是：1）确定一组可以预测HL活性水平和相关脂蛋白表型的遗传标记。 2）定义与心血管疾病风险相关的所有肝脂肪酶基因变体。 3）识别并表征调节肝脂肪酶基因表达的转录因子。 4）确定在人类受试者中，脂质代谢和胰岛素抵抗对HL活性的影响。这些研究的结果将为HL活性和相关血浆脂蛋白谱的个体变异的代谢和分子碱基提供见解。调节HL活性的关键转录因子可以用作诱导有利的脂蛋白谱的新药物的靶标。遗传标记对于预测心血管风险以及对治疗的反应将很有价值。