Saturated Fat and Protein Effects on Atherogenic Dyslipidemia

描述(由申请人提供)：本项目的总体目标是测试饱和脂肪(SF)对心血管疾病(CVD)风险的脂蛋白标记物的影响受饮食蛋白质食物来源影响的假设。越来越多的流行病学证据表明，与白肉或非肉类食品相比，食用红肉与心血管疾病的发病率更高。来自我们小组的初步证据为这种关联的有效性提供了病理生理学支持，即高牛肉饮食比我们观察到的混合蛋白饮食对脂蛋白测量心血管疾病风险的有害影响更大。具体地说，我们发现，高蛋白、高SF和中等红肉含量的饮食选择性地诱导中密度脂蛋白(IDL)和较大的低密度脂蛋白颗粒(已被发现与较小的低密度脂蛋白相比，与心血管疾病风险的相关性要弱得多)的增加。相比之下，我们小组最近的一项研究发现，在类似SF摄入量的情况下，高牛肉摄入量会导致中小型低密度脂蛋白颗粒水平优先增加，这两者都与心血管疾病的发生密切相关。然而，到目前为止，还没有研究直接比较红肉和其他蛋白质食物来源在高饱和脂肪摄入量和低饱和脂肪摄入量情况下的脂蛋白效果。我们特别假设，当蛋白质的主要食物来源是红肉而不是白肉(家禽)或非肉类食品时，SF导致的血浆低密度脂蛋白胆固醇(C)和载脂蛋白B水平的增加更大，这是由于中小型低密度脂蛋白颗粒水平的增加。因此，我们提出了一项临床试验，将180名健康男性和女性随机分为高SF(15%)和低SF(7%)两组，在每组中，按随机顺序分别食用等量的来自红肉、白肉和非肉类来源的蛋白质的日粮，持续4wk。我们的具体目标将测试：(1)与其他蛋白质食物来源相比，红肉饮食是否会导致更高的低密度脂蛋白-C、载脂蛋白B、中小型低密度脂蛋白颗粒和总/高密度脂蛋白-C水平；(2)在低SF条件下，饮食蛋白质来源与这些指标中的任何一个都不相关；(3)在白肉和非肉类日粮中，高SF与低SF的低密度脂蛋白-C的升高主要是由于IDL和/或大的低密度脂蛋白的增加，而在红肉的情况下，中小低密度脂蛋白的额外增加将导致载脂蛋白B的更大的增加。除了这些目的，我们还将测试饮食对含载脂蛋白亚类的影响的可能的代谢决定因素，包括肝素后血浆肝脂酶活性(这对产生较小的低密度脂蛋白至关重要)，以及外周血单核细胞评估的低密度脂蛋白受体活性，该系统被证明反映了生理上相关的低密度脂蛋白受体调节。最后，我们将检查饮食对心血管疾病风险的其他代谢生物标记物的潜在影响，包括高密度脂蛋白亚类和载脂蛋白、HOMA-IR评估的胰岛素敏感性、包括CRP和多种细胞因子在内的炎症指标，以及使用无创指尖方法的内皮功能。

DESCRIPTION (provided by applicant): The overall objective of this project is to test the hypothesis that the effects of saturated fat (SF) on lipoprotein markers of cardiovascular disease (CVD) risk are influenced by food sources of dietary protein. There is growing epidemiological evidence that consumption of red meat is associated with greater incidence of CVD than either white meat or non-meat foods. Pathophysiological support for the validity of this association is provided by preliminary evidence from our group that a high beef diet has a more deleterious effect on lipoprotein measures of CVD risk than we have observed for mixed protein diets. Specifically, we have found that a high protein, high SF diet with a moderate red meat content selectively induces increases in intermediate density lipoproteins (IDL) and larger LDL particles that have been found to be much more weakly associated with CVD risk than smaller LDL. In contrast, a more recent study from our group has found that, with a similar intake of SF, high beef consumption results in a preferential increase in levels of small and medium sized LDL particles, both of which are strongly related to incident CVD. To date however, no studies have directly compared the lipoprotein effects of red meats with other food sources of protein in the context of both high and low saturated fat intake. We specifically hypothesize that increases in plasma levels of LDL cholesterol (C), and apolipoprotein (apo) B, induced by SF are greater when the major food source of protein is red meat rather than either white meat (poultry) or non-meat foods, and that this is due to increased levels of small and medium sized LDL particles. We therefore propose a clinical trial in which 180 healthy men and women will be randomized to high SF (15%) or low SF (7%) diet groups, and within each group, consume diets with equivalent amounts of protein derived from red meat, white meat, and non-meat sources for 4 wk each in random order. Our Specific Aims will test whether: (1) with high SF, the red meat diet, compared to the other food sources of protein, will result in higher levels of LDL-C, apoB, small and medium sized LDL particles, and total/HDL-C; (2) with low SF, dietary protein source will not be related to any of these measurements; (3) with both the white meat and non-meat diets, increased LDL-C with high vs. low SF will be due primarily to increases in IDL and/or large LDL, whereas with red meat the additional increase in small and medium LDL will result in greater increases in apoB. In addition to these aims we will test for possible metabolic determinants of dietary effects on apoB-containing lipoprotein subclasses, including post-heparin plasma hepatic lipase activity, which is critical for production of smaller LDL, and LDL receptor activity as assessed in peripheral blood mononuclear cells, a system demonstrated to reflect physiologically relevant LDL receptor regulation. Finally, we will examine potential dietary influences on other metabolic biomarkers of CVD risk, including HDL subclasses and apoproteins, insulin sensitivity as assessed by HOMA-IR, measures of inflammation including CRP and multiple cytokines, and endothelial function using a non-invasive fingertip method.