ApoE isoforms, fatty acid metabolism and atherosclerosis
Initial Award Abstract
Cigarette smoking contributes to the development of atherosclerosis, premature heart disease, and stroke. Although the exact mechanisms are not known, they likely involve a combination of changes made to cells in the blood vessel walls and to the metabolism of lipoprotein particles that carry fat in the blood. These changes lead to atherosclerosis, to the deposition of fat in cells of the artery walls and to the formation of blood clots, which results in heart attacks and strokes. Understanding the processes that alter the progression of atherosclerosis are critical for treating these diseases effectively.
One protein that is important in preventing atherosclerosis and heart disease is apolipoprotein (apo) E. This protein, a component of plasma lipoproteins, assists in the processing of lipoproteins and in removing them from the blood. When apoE expression is eliminated in mice, plasma cholesterol levels rise, and the mice develop atherosclerosis. When apoE is produced at very low levels in these mice, development of disease is reduced. In humans, the situation is a little more complicated because apoE exists in three different forms, called apoE2, apoE3, and apoE4, which vary by single amino acid changes in their structure. These forms of apoE differ in their effects on lipoprotein metabolism and atherosclerosis. The mechanisms that lead to these differences are not completely understood. We discovered that these forms of apoE have different effects on the uptake of free fatty acids (a type of fat) by cells, which might contribute to their differential effects on the development of disease. Free fatty acid uptake is increased with apoE2 and decreased with apoE4 as compared to the uptake in the presence of apoE3, the most common form of apoE. The studies in this proposal are designed to determine the reason for these effects on fat metabolism and to examine the effects of these differences on the metabolism of fat in experimental animals. The results of these studies will increase our understanding of the role of apoE in fat metabolism and in the prevention of premature disease. |