This research is an investigation of the kinetics of apolipoproteins in normal and hyperlipemic subjects. Previous kinetics studies of the metabolism of a single or pair of apolipoproteins have been reported from a number of laboratories. We shall examine the kinetics of apoA-I, A-II, B, E, and the individual C apoproteins simultaneously in a single subject to investigate their coordinated metabolism, it being our belief that apolipoproteins function as an integrated system during lipid metabolism. These kinetic studies primarily utilize 3H-leucine as an endogenous amino acid tracer incorporated into all the apoproteins. Where appropriate 125I-apoproteins may also be used as exogenous tracers to examine a particular reaction. Following IV tracer injection, repeated blood samples will be drawn over 2 wks., plasma lipoprotein classes will be isolated, and apolipoproteins will be separated on acrylamide gels. The protein bands will be cut from the gels, hydrolyzed with HC1, and leucine specific activity measured. Simultaneous kinetic data will thus be obtained on many apoproteins, and these data will be analyzed by multicompartmental modeling, using the SAAM program, in collaboration with Dr. Mones Berman at NIH. We will investigate apolipoprotein metabolism in a limited group of normal, familial hypercholesterolemic heterozygotes, familial hypertriglyceridemic and familial, diabetic hypertriglyceridemic subjects. In an effort to differentiate tracer from chemical reaction rate constants each subject will be studied under two separate metabolic states induced by either a dietary or a pharmacologic perturbation. This research extends our investigation of apolipoprotein kinetics permitting us to examine the coordinated functioning of multiple apolipoproteins and to measure changes occurring in this system in differing metabolic states.