Hyperhomocysteinemia and HDL Metabolism

高同型半胱氨酸血症和高密度脂蛋白代谢

• 批准号: 8605915
• 负责人: Hong Wang
• 金额: $ 52.27万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-16 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605915
• 关键词: Affect; Anabolism; Animals; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biochemistry; Biological Assay; Biological Models; Blood Vessels; Cardiovascular Diseases; Catabolism; Cholesterol; Coronary heart disease; DNA Methylation; Development; Dyslipidemias; Endothelial Cells; Enzymes; Fatty Liver; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoprotein therapy; High Density Lipoproteins; Homocysteine; Homocystine; Homocystinuria; Human; Hyperhomocysteinemia; Hyperlipidemia; Knowledge; Label; Link; Lipase; Low Density Lipoprotein Receptor; Maps; Mediating; Medical; Metabolism; Modeling; Molecular; Molecular Target; Mus; Particle Size; Patients; Plasma; Proteins; Radiolabeled; Regulation; Reporting; Risk Factors; Role; Smoking; Structural Protein; Structure; Testing; Therapeutic; Transgenic Mice; Translations; Tritium; Vitamins; Water; acetyl-LDL; apolipoprotein Lp(a+); base; cofactor; fast protein liquid chromatography; gene therapy; in vivo; lipid metabolism; macrophage; novel; particle; promoter; public health relevance; radiotracer; reverse cholesterol transport; small hairpin RNA; therapeutic target; vector

DESCRIPTION (provided by applicant): Hyperhomocysteinemia (HHcy) is an important non-lipid risk factor for cardiovascular disease (CVD). At present, our mechanistic knowledge of HHcy's correlation with dyslipidemia and the development of atherosclerosis is limited. Notwithstanding, it has been suggested that HHcy affects hepatic lipid metabolism, thereby contributing to fatty liver, a condition described in humans and animals with HHcy. Our previous findings suggested that plasma HHcy levels are significant negative correlated with plasma HDL-C and apolipoprotein AI (apoA-I), a predominant structural protein in HDL particles and cofactor for HDL maturation, in patients with coronary heart disease (CHD) and in atherosclerosis mice. We also found that severe HHcy is associated with increased HDL-C turnover and increased protein levels of hepatic/vascular endothelial lipase (EL), an HDL degradation enzyme in mice. Because the mechanistic link between HHcy and HDL dysfunction has never been studied, we plan to investigate the role and mechanism of HHcy-induced HDL dysfunction in our newly established severe HHcy models with double gene deficiency for Cystathionine ¿-synthase (CBS) which degrade homocysteine (Hcy), and either apolipoprotein E (ApoE) or low density lipoprotein receptor (LDLR), and with an inducible human CBS gene (Tg-hCBS ApoE-/- Cbs-/-, Tg- hCBS Cbs-/-, and Ldlr-/- Cbs-/+). These set of transgenic mice can circumvent the potential limitations of different model system and are valid for assessing the role and mechanistic links of HHcy-HDL metabolism with/without hyperlipidemia and with/without apoE deficiency. The central hypothesis to be tested in this proposal is that HHcy causes ApoA1 reduction and EL activation, resulting in reduced HDL maturation and increased HDL degradation, leading to impaired reverse cholesterol transport (RCT) contributing to the development of atherosclerosis. We proposed in Aim 1 to determine the effect of HHcy on HDL biosynthesis, catabolism, and function in our newly three developed HHcy models, in Aim 2 to identify molecular targets and underlying biochemical basis mediating HHcy-altered HDL metabolism, and in Aim 3 to reverse HHcy, ApoA1 deficiency or EL activation, and to examine the effect on HDL-raising/function and atherosclerosis. The goal of this proposal is to investigate the role of HHcy in HDL metabolism, in the hope to identify the underlying molecular mechanisms and novel therapies. If the key steps in Hcy-induced dyslipidemia and atherosclerosis can be identified, new genetic or pharmacological therapeutic targets can be utilized for treatment.

描述（由申请人提供）：高同型半胱氨酸血症（HHcy）是心血管疾病（CVD）的重要非脂质危险因素。目前，我们对HHcy与血脂异常和动脉粥样硬化发展相关的机制了解有限。尽管如此，有人认为HHcy会影响肝脏脂质代谢，从而导致脂肪肝，这是人类和动物患有HHcy的一种情况。我们之前的研究结果表明，在冠心病患者和动脉粥样硬化小鼠中，血浆HHcy水平与血浆HDL- c和载脂蛋白AI （apoA-I）呈显著负相关，载脂蛋白AI是HDL颗粒中的主要结构蛋白和HDL成熟的辅助因子。我们还发现，在小鼠中，严重的HHcy与HDL- c转换增加和肝脏/血管内皮脂肪酶（EL）蛋白水平升高有关，EL是一种HDL降解酶。由于HHcy和HDL功能障碍之间的机制联系从未被研究过，我们计划在我们新建立的具有降解同型半胱氨酸（Hcy）、载脂蛋白E （ApoE）或低密度脂蛋白受体（LDLR）双基因缺陷的严重HHcy模型中研究HHcy诱导的HDL功能障碍的作用和机制，并诱导人类CBS基因（Tg-hCBS ApoE-/- CBS -/-、Tg-hCBS CBS -/-和LDLR -/- CBS -/+）。这组转基因小鼠可以规避不同模型系统的潜在局限性，对于评估伴/不伴高脂血症和伴/不伴apoE缺乏的HHcy-HDL代谢的作用和机制联系是有效的。本研究要验证的中心假设是，HHcy导致ApoA1减少和EL激活，导致HDL成熟减少和HDL降解增加，导致胆固醇逆向转运（RCT）受损，从而促进动脉粥样硬化的发展。我们在Aim 1中提出在我们新开发的三种HHcy模型中确定HHcy对HDL生物合成、分解代谢和功能的影响，在Aim 2中确定介导HHcy改变HDL代谢的分子靶点和潜在的生化基础，在Aim 3中提出逆转HHcy、ApoA1缺乏或EL激活，并研究对HDL升高/功能和动脉粥样硬化的影响。本提案的目的是调查