Lp(a) and Oxidized Phospholipids - Impact of Diets

项目摘要/摘要 血浆脂蛋白(A)水平升高[Lp(A)]是心血管疾病的独立致病危险因素 疾病(CVD)。建议改变生活方式，包括改变饮食，作为治疗的一线方法。 降低心血管疾病风险。降低饱和脂肪酸(SFA)并用不饱和脂肪酸取而代之的饮食指南 脂肪或复合碳水化合物主要针对低密度脂蛋白胆固醇(LDL-C)。在少数人中 在评估Lp(A)水平的饮食研究中，发现随着SFA减少，Lp(A)水平持续上升 入口处。由于LPA基因控制Lp(A)水平，而且极少数非遗传因素影响Lp(A)，因此这种饮食介导 效果显著。重要的是，Lp(A)水平的升高与SFA减少的效果相反 低密度脂蛋白-C这一矛盾发现背后的机制(S)以及减少SFA如何影响 Lp(A)血浆水平以外的致动脉粥样硬化特性尚不清楚。Lp(A)携带了大部分流通 促炎症和促动脉粥样硬化氧化磷脂(OxPL)和Lp(A)的致动脉粥样硬化作用是由其介导的 OxPL含量。尽管如此，对于当膳食SFA减少时OxPL会发生什么，以及它的 主要载脂蛋白载体增多。这项建议将弥合这些知识差距，并获得更多 根据当前饮食指南，通过减少SFA来控制心血管疾病风险的完整图景。 中心假设-Lp(A)-OxPL含量随着膳食SFA替代而增加 降低低密度脂蛋白-C对心血管疾病风险的有益影响-将通过在 最大和最多样化的平台，包括三个由美国国立卫生研究院资助、控制良好的代谢性喂养试验 (增量1、增量2和Get-Readi)。具体地说，Lp(A)-OxPL的变化动态 将使用定量(总浓度)(目标1)和定性(亚种)来评估SFA的减少 成分)(目标3)在健康和代谢障碍的个人中采用的方法。更换 减少SFA的策略(不饱和脂肪与复合碳水化合物)和遗传变异性通过 将测试载脂蛋白(A)大小的多态作为反应调节剂。特定子组(例如， 民族/种族，有代谢负担和没有代谢负担的人)谁可能受益最少(或最多) 将确定减少SFA摄入量的通用饮食指南(目标2)。作为临床实验室的价值 低密度脂蛋白-C包括Lp(A)胆固醇，SFA降低对这两种脂蛋白的相反作用，因此， 可能会导致对真实的低密度脂蛋白-C反应的不准确估计。这一关键问题将在更多 细节。这些发现源自最大规模和最多样化的数据汇编，将改善 了解一种可增强脂蛋白(A)致动脉粥样硬化潜能的常见非药物疗法 超过了它的血浆水平。最终，这将有助于采用精确营养作为心脏健康的一部分 改善心血管疾病风险预防和管理的生活方式。

PROJECT SUMMARY/ABSTRACT An elevated level of plasma lipoprotein(a) [Lp(a)] is an independent causal risk factor for cardiovascular disease (CVD). Lifestyle modifications, including dietary changes, are recommended as first line therapy to reduce CVD risk. Dietary guidelines to lower saturated fatty acids (SFA) and replace them with unsaturated fats or complex carbohydrates target primarily low-density lipoprotein cholesterol (LDL-C). In the small number of dietary studies that assessed Lp(a) level, a consistent increase was found in response to reduction in SFA intake. As LPA gene controls Lp(a) level and very few non-genetic factors impact Lp(a), this diet-mediated effect is notable. Importantly, the increase in Lp(a) level is a counter observation to the effect of SFA reduction on LDL-C. The mechanism(s) underlying this paradoxical finding and furthermore how SFA reduction affects Lp(a) atherogenic properties beyond its plasma level remains unknown. Lp(a) carries the majority of circulating proinflammatory and proatherogenic oxidized phospholipids (OxPL) and Lp(a) atherogenicity is mediated by its OxPL content. Despite this, little is known about what happens to OxPL when dietary SFA is reduced and its major lipoprotein carrier is increased. This proposal will bridge these knowledge gaps and obtain a more complete picture of CVD risk manipulation through SFA reduction consistent with current dietary guidelines. The central hypothesis—Lp(a)-OxPL content is increased with dietary SFA replacement diminishing the beneficial effect of LDL-C lowering on CVD risk—will be tested through a comprehensive research in the largest and most diverse platform consisting of three NIH-funded well-controlled metabolic feeding trials (DELTA 1, DELTA 2, and GET-READI). Specifically, the dynamics of changes in Lp(a)-OxPL in response to SFA reduction will be assessed using quantitative (total concentration) (Aim 1) and qualitative (subspecies composition) (Aim 3) approaches in both healthy and metabolically challenged individuals. Replacement strategies for SFA reduction (unsaturated fats vs. complex carbohydrate) and genetic variability modelled via the apolipoprotein(a) size polymorphism will be tested as response modulators. Specific subgroups (e.g., ethnic/racial, those with and without metabolic burden) who may benefit the least (or the most) from the generalized dietary guidelines to reduce SFA intake will be identified (Aim 2). As clinical laboratory values for LDL-C include Lp(a) cholesterol, the opposing effect of SFA reduction on these two lipoproteins, therefore, likely results in an inaccurate estimation of the true LDL-C response. This critical issue will be mapped in more detail. The findings originating in the largest and most diverse compilation of data will improve the understanding of a common non-pharmacological therapy that may enhance the atherogenic potential of Lp(a) beyond its plasma level. Ultimately, this will assist in adopting precision nutrition as part of a heart-healthy lifestyle for an improved CVD risk prevention and management.