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检验饱和脂肪（SF）对心血管疾病（CVD）风险脂蛋白标志物的影响受膳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，食用红肉比食用白色肉类或非肉类食物与心血管疾病的发病率更高有关。我们小组的初步证据表明，高牛肉饮食对心血管疾病风险的脂蛋白指标的有害影响比我们观察到的混合蛋白饮食更大，这为这种关联的有效性提供了病理生理学支持。具体来说，我们发现，高蛋白，高SF饮食与中等红肉含量选择性地诱导增加中密度脂蛋白（IDL）和较大的LDL颗粒，已被发现与CVD风险比较小的LDL弱得多。相比之下，我们小组最近的一项研究发现，在SF摄入量相似的情况下，高牛肉摄入量会导致中小尺寸LDL颗粒水平的优先增加，这两者都与CVD事件密切相关。然而，到目前为止，还没有研究直接比较红肉与其他食物来源的蛋白质在高和低饱和脂肪摄入量的背景下的脂蛋白效应。我们特别假设，当蛋白质的主要食物来源是红肉而不是白色肉（家禽）或非肉类食物时，SF诱导的血浆LDL胆固醇（C）和载脂蛋白（apo）B水平升高更大，这是由于中小尺寸LDL颗粒水平升高。因此，我们提出了一项临床试验，其中180名健康男性和女性将被随机分配到高SF（15%）或低SF（7%）饮食组，并在每组内，消费与等量的蛋白质来源于红肉，白色肉，和非肉类来源的饮食4周，每个随机顺序。我们的特定目标将测试：（1）与其他蛋白质食物来源相比，高SF，红肉饮食是否会导致更高水平的LDL-C，apoB，中小尺寸LDL颗粒和总/HDL-C;（2）低SF，饮食蛋白质来源与这些测量无关;（3）对于白色肉和非肉饮食，高SF与低SF的LDL-C增加主要是由于IDL和/或大LDL的增加，而对于红肉，小LDL和中LDL的额外增加将导致apoB的更大增加。除了这些目标之外，我们还将测试饮食对含apoB脂蛋白亚类影响的可能代谢决定因素，包括肝素后血浆肝脂肪酶活性（这对于产生较小的LDL至关重要）和外周血单核细胞中评估的LDL受体活性，该系统被证明反映了生理相关的LDL受体调节。最后，我们将研究饮食对CVD风险的其他代谢生物标志物的潜在影响，包括HDL亚类和载脂蛋白，通过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，以及使用非侵入性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.