Elevated plasma cholesterol level is a major risk factor for the development of coronary heart disease. One factor known to increase plasma cholesterol level is dietary cholesterol intake, however, not all individuals increase plasma cholesterol levels in response to cholesterol intake. Much of the variation in response is due to compensatory changes in de novo cholesterol synthesis. Indeed, de novo synthesis accounts for a much greater percentage of whole body cholesterol than dietary sources. Despite this, little is known about de novo synthesis in humans because of the difficulty in measuring synthesis in vivo. The investigators have developed a very sensitive method to measure cholesterol synthesis in vivo based on the incorporation of deuterium from body water. This method can be used to measure cholesterol synthesis over periods of hours or a day. The investigators have demonstrated that human cholesterol synthesis has a strong diurnal rhythm varying from near zero during the afternoon to nearly twice the daily average in the early morning. The investigators have also shown that synthesis is inhibited by 95 percent after a 24 hour fast. Herein, the investigators propose to apply this deuterium incorporation method in studies to elucidate the mechanisms controlling these large acute changes in cholesterol synthesis. The investigators will extend current models of cholesterol metabolism by measuring the relative contribution of de novo synthesis in the central, rapidly miscible cholesterol pool and in the slowly equilibrating side pools. The investigators will extend knowledge of cholesterol regulation by systematically altering sleep, light/dark, and feeding cycles to determine which factors entrain the diurnal rhythm of cholesterol synthesis. Finally, the investigators will develop the deuterium incorporation method as a quantitative method that will offer an alternative to the cholesterol balance method for investigating cholesterol metabolism. The deuterium incorporation method for the first time provides a quantitative, in vivo measure of human cholesterol synthesis over periods as short as hours. This is a powerful new tool for the study of cholesterol metabolism.
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