Hyperhomocysteinemia and HDL Metabolism

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）的重要非脂质风险因素。目前，我们对高同型半胱氨酸与血脂异常及动脉粥样硬化发生发展的机制认识有限。尽管如此，已经表明HHcy影响肝脏脂质代谢，从而导致脂肪肝，这是在患有HHcy的人类和动物中描述的病症。我们的前期研究表明，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。我们还发现，严重的高同型半胱氨酸是与增加高密度脂蛋白胆固醇周转和增加蛋白水平的肝/血管内皮脂肪酶（EL），高密度脂蛋白降解酶在小鼠。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严重HHcy模型中研究HHcy诱导的HDL功能障碍的作用和机制，该模型具有胱硫醚双基因缺陷。- 降解高半胱氨酸（Hcy）的合成酶（CBS），以及载脂蛋白E（ApoE）或低密度脂蛋白受体（LDLR），和诱导型人CBS基因（Tg-hCBS ApoE-/- Cbs-/-、Tg-hCBS Cbs-/-和Ldlr-/- Cbs-/+）。这些转基因小鼠组可以规避不同模型系统的潜在限制，并且对于评估具有/不具有高脂血症和具有/不具有apoE缺陷的HHcy-HDL代谢的作用和机制联系是有效的。在该提议中要检验的中心假设是，HHcy导致ApoA 1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。我们在目标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、代谢和功能的影响，在目标2中确定介导HHcy改变的HDL代谢的分子靶点和潜在的生化基础，在目标3中逆转HHcy、ApoA 1缺乏或EL激活，并检查对HDL升高/功能和动脉粥样硬化的影响。这项提案的目的是调查 HHcy在高密度脂蛋白代谢中的作用，希望确定潜在的分子机制和新的治疗方法。如果可以确定Hcy诱导的血脂异常和动脉粥样硬化的关键步骤，则可以利用新的遗传或药理学治疗靶点进行治疗。

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.