Post-Translational Regulation of Lipid Metabolism

脂质代谢的翻译后调控

• 批准号: 9889993
• 负责人: Elizabeth Joanna Tarling
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889993
• 关键词: Animals; Antisense Oligonucleotides; Atherosclerosis; Attenuated; Blood Circulation; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Surface Receptors; Cell surface; Cessation of life; Cholesterol; Cholesterol Homeostasis; Cytoplasmic Tail; Data; Diabetes Mellitus; Disease; Disease model; Dyslipidemias; Endocytosis; Gene Silencing; Genes; Glucose; Health; Heart Diseases; Hepatic; Heritability; Human; Human Genome; Hypertension; In Vitro; Knockout Mice; LDL Cholesterol Lipoproteins; Lipids; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Obesity; Pathway interactions; Plasma; Post-Translational Regulation; Proteomics; Public Health; Recycling; Regulation; Regulatory Pathway; Risk Factors; Site-Directed Mutagenesis; Structure; Testing; Therapeutic; Tissues; Triglycerides; Ubiquitination; United States; base; cardiovascular disorder risk; cardiovascular risk factor; clinical care; embryonic stem cell; feeding; genome wide association study; in vivo; knockout animal; lipid metabolism; loss of function; novel; overexpression; protein expression; receptor; receptor expression; small molecule; therapeutic target; tool; trait; uptake; western diet

ABSTRACT Elevated plasma cholesterol, triglycerides and metabolic complications such as obesity are among the most important risk factors for cardiovascular disease (CVD). Understanding the factors and mechanisms that regulate plasma low-density lipoprotein (LDL) cholesterol levels is of the utmost importance. Increasing hepatic LDL receptor (LDLR) expression leads to increased uptake of LDL cholesterol from the circulation, and has been a successful therapeutic strategy for treating CVD and dyslipidemia. Here, we identify a novel gene that regulates hepatic LDLR and plasma LDL cholesterol levels that is also a locus for LDL-C levels in human Genome-wide Association Studies. In extensive preliminary data, we show that overexpression and silencing (using antisense oligonucleotides, ASOs) of the candidate gene in vivo also alters plasma total and LDL cholesterol levels, and reciprocally regulates the LDLR, suggesting the mechanism of action is directly through targeting the LDLR. In Specific Aim 1 we will determine the molecular mechanism and structural requirements of the regulation of LDLR protein expression and plasma LDL cholesterol levels. In Specific Aim 2, we will use complimentary in vivo gain- and loss-of-function models, including tissue-specific knockout mice and ASOs, to determine the therapeutic potential of specific ASO silencing agents in a relevant disease model of atherosclerosis. In the current proposal we describe a novel post-translational pathway that modulates plasma cholesterol homeostasis. Our findings identify a novel post- translational regulation that can be targeted with ASO silencing agents and therefore has significant therapeutic potential.

摘要 血浆胆固醇、甘油三酯和代谢并发症（如肥胖）升高是其中之一。 心血管疾病（CVD）最重要的危险因素。了解这些因素， 调节血浆低密度脂蛋白（LDL）胆固醇水平的机制是最重要的 重要性肝脏LDL受体（LDLR）表达增加导致LDL摄取增加 胆固醇的循环，并已成为一种成功的治疗策略，用于治疗心血管疾病， 血脂异常在这里，我们确定了一个新的基因，调节肝脏LDLR和血浆LDL胆固醇 在人类全基因组关联研究中，LDL-C水平也是一个位点。在广泛 初步数据显示，过表达和沉默（使用反义寡核苷酸， 候选基因在体内的表达（ASO）也会改变血浆总胆固醇和LDL胆固醇水平， LDLR调节LDLR，表明作用机制是直接通过靶向 LDLR。在具体目标1中，我们将确定 调节LDLR蛋白表达和血浆LDL胆固醇水平。在Aim Specific 2中，我们 将使用免费的体内功能获得和丧失模型，包括组织特异性敲除 小鼠和ASO，以确定特异性阿索沉默剂在相关疾病中的治疗潜力。 动脉粥样硬化的疾病模型。在目前的建议中，我们描述了一种新的翻译后 调节血浆胆固醇稳态的途径。我们的研究发现了一种新的后- 翻译调控可以用阿索沉默剂靶向，因此具有显著的 治疗潜力