Lp(a) and Oxidized Phospholipids - Impact of Diets

项目概要/摘要 血浆脂蛋白（a）[Lp（a）]水平升高是心血管疾病的独立因果危险因素， 疾病（CVD）。生活方式的改变，包括饮食的改变，建议作为一线治疗， 降低CVD风险。降低饱和脂肪酸（SFA）并以不饱和脂肪酸替代的膳食指南 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 在评估Lp（a）水平的膳食研究中，发现SFA减少后Lp（a）水平持续升高 摄入由于LPA基因控制Lp（a）水平，而影响Lp（a）水平的非遗传因素很少，因此这种饮食介导的 效果显著。重要的是，Lp（a）水平的升高与SFA减少的效果相反 对LDL-C的影响这一矛盾发现的机制以及SFA减少如何影响 脂蛋白（a）在血浆水平以外的致动脉粥样硬化特性仍不清楚。Lp（a）携带大部分的循环 促炎和促动脉粥样硬化的氧化磷脂（OxPL）和Lp（a）的致动脉粥样硬化性是由其 OxPL含量。尽管如此，很少有人知道当膳食SFA减少时OxPL会发生什么， 主要脂蛋白载体增加。该提案将弥合这些知识差距，并获得更多 通过与当前膳食指南一致的SFA减少来控制CVD风险的完整画面。 中心假设-Lp（a）-OxPL含量随着膳食SFA替代减少而增加， 降低LDL-C对CVD风险的有益作用-将通过一项全面的研究进行测试， 最大和最多样化的平台，由三个NIH资助的控制良好的代谢喂养试验组成 （DELTA 1、DELTA 2和GET-READI）。具体而言，Lp（a）-OxPL响应于 将使用定量（总浓度）（目标1）和定性（亚种）评估SFA减少 组成）（目标3）在健康和代谢挑战的个体中接近。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， 将载脂蛋白（a）大小多态性作为应答调节剂进行测试。特定的亚组（例如， 种族/人种，有和没有代谢负担的人），他们可能从治疗中获益最少（或最多）。 将确定减少SFA摄入量的通用膳食指南（目标2）。临床实验室检查值 LDL-C包括Lp（a）胆固醇，SFA减少对这两种脂蛋白的相反作用，因此， 可能导致对真实LDL-C反应的估计不准确。这一关键问题将在更多的 详细来自最大和最多样化的数据汇编的调查结果将改善 了解一种可能增强Lp（a）致动脉粥样硬化潜力的常见非药物治疗 超过了血浆水平最终，这将有助于采用精确营养作为心脏健康的一部分。 改善生活方式，以改善CVD风险预防和管理。

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.