How does dietary carbohydrate influence the formation of an atherogenic lipoprotein phenotype?

早产儿心血管疾病(CVD)是英国三分之一的死亡原因，并给NHS带来了巨大的经济负担。它的患病率正在以惊人的速度增长，因为与肥胖和糖尿病等相关疾病相关的心血管疾病风险。预防肥胖和降低心血管疾病风险的关键公共卫生营养战略是用碳水化合物取代膳食脂肪，主要是饱和脂肪。然而，研究表明，当脂肪被碳水化合物取代时，患心血管疾病的风险实际上会增加。这种影响与碳水化合物的质量有关，更具体地说，与蔗糖和果糖等单糖摄入量的增加有关。后者在我们的饮食中大量存在，当过量摄入时，已被证明会增加血液和肝脏等组织中的脂肪(甘油三酯)的数量。这种脂肪的积累可能会导致一种代谢缺陷，这种缺陷在肥胖和糖尿病中发生，称为胰岛素抵抗，即身体组织对胰岛素的作用变得没有反应。胰岛素抵抗是一种非常常见的疾病，它会导致胆固醇代谢的不利变化，从而增加患心血管疾病的风险。这些变化包括肥胖和糖尿病患者血液中高水平存在的被称为小而密集的低密度脂蛋白(SdLDL)的颗粒增加，并将胆固醇输送到血管壁，导致心血管疾病。饮食中的碳水化合物究竟如何增加血液和肝脏等组织中的脂肪量，并在胰岛素抵抗的情况下导致高水平的sdLDL，目前尚不清楚。对这些问题的回答将有助于更好地理解为什么碳水化合物的质量与心血管疾病风险的增加有关。它们还将为影响未来公众健康的饮食建议提供有价值的信息。这项研究计划的目的是确定高单糖饮食碳水化合物的质量增加血脂并影响sdLDL形成的代谢机制。这将在有胰岛素抵抗和肝脏脂肪增加证据的人身上进行研究。这个研究小组代表了自由生活和健康的英国人，他们患心血管疾病的风险更高。众所周知，他们对饮食碳水化合物的不利影响也很敏感，因此根据这项研究的结果改变他们的饮食将获得最大的好处。我们的假设是，高单糖饮食会增加肝脏分泌的富含甘油三酯的颗粒(称为VLDL1颗粒)，从而增加sdLDL颗粒的数量，这种情况在胰岛素抵抗和适度肝脏脂肪的人中会发生得更多。这项研究将比较两种高糖和低糖但仍代表英国饮食的饮食。这将是一项自由生活的研究，食物供应给志愿者，并在他们自己的家里消费。心血管疾病风险增加的受试者将被细分为两组，根据无创性MRI扫描的测量，肝脏脂肪含量低和中等升高。在低单糖的磨合饮食之后，受试者将被随机分成两组，要么继续这种磨合饮食，要么改用单糖含量高的饮食12周。然后，受试者切换到另一种饮食，持续12周。将在每种饮食结束时进行代谢调查，以确定饮食增加血脂和形成sdLDL的机制。这将涉及给受试者提供稳定的istope作为跟踪标签，以测量肝脏产生甘油三酯的速度，并跟踪富含甘油三酯的VLDL1的新陈代谢，以准确确定在两种饮食条件下这是如何形成sdLDL的。这些方法对志愿者没有风险，并将提供独特的信息来减少饮食中碳水化合物对心血管疾病的不利影响。

Premature cardiovascular disease (CVD) is responsible for 1 in 3 deaths in the UK, and imposes an enormous financial burden on the NHS. Its prevalence is increasing at an alarming rate because of the CVD risk associated with obesity and related conditions such as diabetes. A key public health nutritional strategy for preventing the development of obesity and reducing CVD risk, is to replace dietary fat, principally saturated fat, with carbohydrate. However, studies have shown that when fat is replaced with carbohydrate, the risk of CVD actually increases. This effect has been linked to the quality of carbohydrate, and more specifically, to an increased intake of simple sugars such as sucrose and fructose. The latter are abundant in our diet and when overconsumed, have been shown to increase the amount of fat (triglyceride) in the blood and in tissues such as the liver. This accumulation of fat can lead to a metabolic defect that occurs in obesity and diabetes called insulin resistance, when tissues in the body become unresponsive to the actions of insulin. Insulin resistance is a very common condition that can produce adverse changes in cholesterol metabolism that increase the risk of developing CVD. These changes include an increase in particles known as small, dense LDL (sdLDL) that are found in high levels in the blood of people with obesity and diabetes, and transport cholesterol into the walls of blood vessels, causing CVD. Exactly how dietary carbohydrate increases the amount of fat in the blood and tissues such as liver, and contributes, with insulin resistance, to high levels of sdLDL is not clear. Answers to these questions would provide a better understanding of why the quality of carbohydrate is associated with increased CVD risk. They would also provide valuable information for influencing future dietary recommendations for public health. The aim of this research proposal is to determine the metabolic mechanisms by which the quality of dietary carbohydrate, high in simple sugars, increases blood fat and influences the formation of sdLDL. This will be studied in people with evidence of insulin resistance and an increased amount of liver fat. This study group is representative of a free-living and otherwise healthy UK population who are at increased risk of CVD. They are also known to be sensitive to the adverse effects of dietary carbohydrate, and thus stand to gain the greatest benefit from changing their diet in line with the results from this study. Our hypothesis states that a diet high in simple sugars will increase the number of sdLDL particles by increasing the amount of triglyceride-rich particles secreted from the liver (called VLDL1 particles), and that this will occur to a greater extent in people with insulin resistance and a moderate amount of liver fat. The study will compare two diets that are high and low in sugars but still representative of the UK diet. It will be a free-living study, with foods being supplied to the volunteers and consumed in their own homes. Subjects at increased risk of CVD will be subdivided into two groups with low and moderately raised liver fat, as measured by non-invasive MRI scanning. After a run-in diet low in simple sugars, subjects will be randomised to either continue on this run-in diet or switch to a diet high in simple sugars for 12 weeks. The subjects then switch to the other diet for another 12 weeks. Metabolic investigations to determine the mechanism by which the diet increases blood fat and forms sdLDL will be carried out at the end of each diet. This will involve giving the subjects stable istopes as trace labels to measure the rate at which triglyceride is produced in the liver, and to follow the metabolism of triglyceride-rich VLDL1 to determine exactly how this forms sdLDL under the two dietary conditions. These methods present no risk to the volunteers and will provide unique information to reduce the adverse effects of dietary carbohydrate on CVD