The metabolic and functional heterogeneity of high density lipoproteins were investigated in a series of in vivo kinetic studies. The two major classes of HDL particles are known as LpA-l and LpA-I,A-ll. A method to isolate these particles was established and then utilized to study their in vivo metabolism. It was demonstrated that the LpA-l particle is more rapidly catabolized from plasma and also undergoes a net conversion to LpA-I,A-ll. Two patients with normotriglyceridemic hypoalphalipoproteinemia were also studied and were found to have more rapid catabolism of both types of particles. These studies enhance our understanding of HDL metabolism. A possible homozygote for familial hyperalphalipoproteinemia has been identified with dramatic elevation in HDL and a family history of longevity on both sides. An in vivo kinetic study in this subject revealed markedly elevated apoA-l production rates with normal apoA-II production. This is the first individual identified with apoA-l overproduction and may lead to the identification of a gene or mutation responsible for regulating apoA-l synthesis. Amino acids labeled with stable isotopes have been used to investigate the in vivo kinetics of a mutant apolipoprotein, apoA-I(Iowa), in a patient heterozygous for the mutation by endogenous labeling of both normal and mutant proteins and then directly comparing their kinetics. It was found that the apoA-I(Iowa) has a substantially faster fractional catabolism, consistent with the hereditary amyloidosis and hypoalphalipoproteinemia found in the kindred. This study demonstrates that the stable isotope method has great potential for the study of the in vivo kinetics of mutant proteins, particularly in heterozygotes.
