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

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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.