This project is designed to investigate the possibility that early development of hypercholesterolemia and atherosclerosis in some people results from genetic reduction of lysosomal acid lipase (AL) activity or neutral cholsteryl esterase (NCE) activity. The former possibility is suggested by the finding that reduced AL activity measured in lymphocytes using 4-me*hylumbelliferyl oleate as substrate is associated with an increased incidence of hypercholesterolemia; family studies have revealed that inherited reduction of AL occurs in some kindreds selected for hypercholesterolemia. These findings will be extended to include other families, and we will attempt to uncover the role of AL activity in modulating serum cholesterol levels. Analogous studies will be done for another major cholesteryl esterase activity, NCE. That inherited variation of AL occurs in the population associated with both rare inborn errors (Wolman disease, cholesteryl ester storage disease) and common disorders (hypercholesterolemia) prompts us to examine the role of other lipolytic enzymes in predisposition to other forms of neutral lipid storage disease.