Mechanisms to Explain Variation in Serum Low Density Lipoprotein Cholesterol Response to Dietary Saturated Fat

血液中胆固醇（也被称为低密度脂蛋白或“坏”胆固醇）水平升高是患心脏病的一个重要风险因素。通过改变我们的饮食和服用某些药物（如他汀类药物）来降低胆固醇水平是一项主要的公共卫生策略，可以降低英国人患心脏病的风险。我们的饮食中有一种被称为饱和脂肪的脂肪（主要存在于肉类和乳制品等动物产品中），它被公认为是导致血液胆固醇升高的主要饮食成分，30多年来，减少饱和脂肪的摄入一直是预防心脏病的饮食指南的主要内容。然而，来自大型、强大的荟萃分析研究的结果显示，没有证据表明摄入饱和脂肪与心脏病发作和中风死亡之间存在直接联系。对这一结果的一种解释是，饱和脂肪和心脏病之间的联系不是直接的，而是依赖于饱和脂肪提高血液胆固醇（LDL-C）水平的能力。这种影响是复杂的，而且因人而异，因为在摄入高饱和脂肪的食物后，新陈代谢和人体吸收和消化胆固醇的方式存在重要差异。这些个体差异使得研究像饱和脂肪这样的饮食因素如何影响大量人群的血液胆固醇变得困难。然而，这些代谢变化可以相对容易地测量，并作为生物标记来确定哪些人对低饱和脂肪饮食反应良好，哪些人反应较差。这项提议的主要目的是测量血液中低密度脂蛋白胆固醇的变化，以应对将饮食中的饱和脂肪量降低到政府建议的心脏病预防水平（低密度脂蛋白筛查研究）。从这项初步研究中，我们将选择一组血液LDL胆固醇高反应组和一组低反应组进行更详细的研究，以确定导致这两组差异的代谢过程（代谢研究）。我们预测，对低饱和脂肪饮食表现出高血液ldl -胆固醇反应的人，其肠道对饮食脂肪的吸收会比低饱和脂肪饮食反应的人更少。我们认为，这种影响可以通过肠道细菌的变化来解释，肠道细菌的变化可以改变胆汁酸的成分，胆汁酸可以促进饮食脂肪的吸收。这也可以用一种被称为肠道通透性的现象来解释，这种现象可能会因食用饱和脂肪而增加。肠道通透性也因人而异，影响脂肪吸收和肠道细菌。此外，我们将测量细胞表面特定受体（低密度脂蛋白受体）的活性，这些受体可以将低密度脂蛋白从血液中清除，并且已经被证明通过食用饱和脂肪含量高的饮食会降低低密度脂蛋白胆固醇（导致低密度脂蛋白胆固醇升高）。最后，在代谢研究中，我们还将使用代谢组学技术对高和低LDL-C应答者的代谢状态进行全面测量。这种方法可以同时测量血液和尿液样本中的数千种代谢物，并检测高反应者和低反应者之间的细微差异（代谢特征），这些差异可以用作对饮食饱和脂肪敏感性的简单生物标志物。这项研究的结果将用于解决为整个人群制定饮食指南的问题，这些指南通常不适用于人口中的某些亚群。这将通过为那些患心脏病风险较高的人提供量身定制的饮食建议来实现，因此他们将获得最大的健康益处。

A raised level of blood cholesterol (also referred to as LDL or 'bad' cholesterol) is an important risk factor for developing heart disease. Lowering cholesterol levels by changing our diet and taking certain medication (e.g. statins) represents a major public health strategy to decrease the risk of developing and suffering from heart disease in the UK population. A type of fat eaten in our diet known as saturated fat (found predominately in animal products such as meat and dairy) is well recognised as the main dietary component responsible for raising blood cholesterol, and reducing its intake has been the mainstay of dietary guidelines for the prevention of heart disease for over 30 years. However, findings from large, powerful studies called meta-analyses show no evidence for a direct link between the intake of saturated fat and deaths from heart attack and stroke. One explanation for this outcome is that the link between saturated fat and heart disease is not a direct one, but relies on the ability of saturated fat to raise blood cholesterol (LDL-C) levels. This effect is complex, and highly variable between individuals because of important differences in metabolism and the way in which our body's absorb and digest cholesterol after eating meals high in dietary saturated fat. These individual differences make it difficult to study how dietary factors like saturated fat influence blood cholesterol in large numbers of people. However, these variations in metabolism can be measured relatively easily and used as biological markers to determine which people will respond well and those who will respond less well to diets which are lower in saturated fat. The main aims of this proposal are to measure variation in blood LDL cholesterol in response to lowering the amount of saturated fat in the diet to the level recommended by the government for heart disease prevention (LDL Screening Study). From this initial study, we will select a group of high responders and a group of low responders in blood LDL cholesterol for a more detailed study to determine the metabolic processes responsible for the variation between these two groups (Metabolic Study). We predict that people who show a high blood LDL-cholesterol response to a diet lower in saturated fat will show a greater reduction in the absorption of dietary fat in their gut than low responders. We believe that this effect may be explained by changes in their gut bacteria, which can alter the composition of compounds called bile acids that promote the absorption of dietary fat. It may also be explained by a phenomenon known as gut permeability which may be increased by eating saturated fat. Gut permeability also differs between individuals and affects fat absorption and gut bacteria. In addition, we will measure the activity of specific receptors on the surface of cells (LDL receptors) that remove LDL from the blood and have been shown to be reduced by eating diets high in saturated fat (causing LDL cholesterol to rise). Finally, in the Metabolic Study we will also undertake a holistic measure of the metabolic state in high and low LDL-C responders using a technique known as metabonomics. This approach can measure thousands of metabolites simultaneously in samples of blood and urine, and detect subtle differences (metabolic signatures) between high and low responders that can be used as simple biomarkers for the sensitivity to dietary saturated fat. The results from this study will be used to overcome the problems of setting dietary guidelines for whole populations, which are frequently inappropriate for some subgroups of people in the population. This will be achieved by the tailoring of dietary advice to those at higher risk of developing heart disease and who therefore stand to gain the greatest benefit to their health.