This proposal will examine the causes of primary hypercholesterolemia (nonfamilial hypercholesterolemia), and it will develop a step-care approach to therapy of this condition. One hundred and sixty patients with primary hypercholesterolemia will be studied. They will first be studied by isotope-kinetic techniques to determine their underlying physiological defect, whether decreased receptor-mediated clearance of LDL, reduced affinity of LDL for receptors, or overproduction of LDL. Family studies will be carried out to determine whether the hypercholesterolemia in some families is inherited as a monogenic disorder. If evidence is obtained for the latter, the underlying metabolic defect will be sought, namely, an abnormality in the primary structure of apolipoprotein B, a reduced ability of cells to generate LDL receptors, an overabsorption of cholesterol, a decreased synthesis of bile acids, or a failure to catabolize saturated fatty acids. In patients with overproduction of LDL, several studies will be done including the composition and lipoprotein content of apolipoprotein E, the interaction of VLDL with cells in culture (fibroblasts and macrophages), and the physical characteristics of LDL. Patients with primary hypercholesterolemia will then enter into a treatment program. The first phase will be diet in which the effectiveness of diets low in fat and high in monounsaturated fats will be compared. The next step will be to study the additional benefit from drugs used in low doses to inhibit the absorption of cholesterol (sitostanol) and bile acids (cholestyramine). Finally, these regimens will be compared to HMG CoA reductase inhibitors (mevinolin). As a last study, the mechanisms of action of mevinolin and cholestyramine will be compared in patients with reduced clearance of LDL, while mevinolin and nicotinic acid will be compared in patients with overproduction of LDL.