Hyperhomocysteinemia and HDL Metabolism

描述(申请人提供)：高同型半胱氨酸血症(HHcy)是心血管疾病(CVD)的一个重要的非脂类危险因素。目前，我们对HHcy与血脂异常的关系以及动脉粥样硬化发展的机制认识还很有限。尽管如此，有人认为HHcy影响肝脏的脂质代谢，从而导致脂肪肝，这是一种在患有HHcy的人和动物中描述的情况。我们以前的发现表明，在冠心病(CHD)患者和动脉粥样硬化小鼠中，血浆HHcy水平与血浆高密度脂蛋白-C和载脂蛋白AI(apoA-I)呈显著负相关。载脂蛋白AI是高密度脂蛋白颗粒中的主要结构蛋白，也是高密度脂蛋白成熟的辅助因子。我们还发现，严重的HHcy与小鼠高密度脂蛋白-C周转增加和肝/血管内皮脂酶(EL)蛋白水平增加有关，EL是一种高密度脂蛋白降解酶。由于HHcy和高密度脂蛋白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诱导的高密度脂蛋白功能障碍的作用和机制，该模型具有降解同型半胱氨酸(Hcy)的胱硫醚合成酶(CBS)和载脂蛋白E(ApoE)或低密度脂蛋白受体(LDLR)的双基因缺失，并带有可诱导的人类CBS基因(TG-HCBS ApoE-/-CBS-/-，TG-HCBS CBS-/-和Ldlr-/-CBS-/+)。这些转基因小鼠可以绕过不同模型系统的潜在限制，可以有效地评估HHcy-HDL代谢在高脂血症/非高脂血症和/或apoE缺乏症中的作用和机制联系。在这项建议中要检验的中心假设是，HHcy导致ApoA1减少和EL激活，导致高密度脂蛋白成熟减少和高密度脂蛋白降解增加，导致胆固醇反向运输(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个HHcy模型中确定HHcy对高密度脂蛋白生物合成、分解代谢和功能的影响，目的2确定介导HHcy改变高密度脂蛋白代谢的分子靶点和潜在的生化基础，目标3逆转HHcy、ApoA1缺乏或EL激活，并检测其对高密度脂蛋白升高/功能和动脉粥样硬化的影响。这项提案的目标是调查 HHcy在高密度脂蛋白代谢中的作用，以期确定其潜在的分子机制和新的治疗方法。如果能够确定Hcy诱导的血脂异常和动脉粥样硬化的关键步骤，就可以利用新的遗传或药物治疗靶点进行治疗。

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.