The transport and metabolism of the plasma lipoproteins secreted by the liver and intestine involves specific apolipoproteins and lipolytic enzymes. To elucidate the metabolic pathways of lipoprotein metabolism in control subjects and patients with dyslipoproteinemias the normal as well as the mutant apolipoproteins must be isolated and characterized. These apolipoproteins may then be used for structural analysis as well as kinetic studies to determine the metabolism of the purified apolipoprotein. Over the last several years the laboratory has systematically isolated the major apolipoproteins from control subjects including apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, D, and E. These apolipoproteins have been used for kinetic studies to establish the metabolic parameters of the individual apolipoproteins in control subjects. Recent studies have been directed toward the isolation of apoA-IV and the kinetic analysis of the individual apoA-IV isoproteins. Kinetic studies established that the apoA-IV-2 isoprotein is more rapidly catabolized than apoA-IV-1. Several different human mutant plasma apolipoproteins have also been isolated and the apoA-I and apoE variants have been particularly interesting. ApoA-I- Iowa contained a single amino acid substitution of a glycine for an arginine at residue 26. Patients with apoA-I Iowa have low plasma HDL levels, hereditary amyloidosis, and severe renal disease. Kinetic studies revealed that the apoA-I Iowa variant was very rapidly catabolized and was the reason for the low plasma levels of HDL in the patients with apoA-I Iowa. The variant A-I Iowa apolipoprotein accumulates in the extracellular space and is the protein moiety in the amyloid. The kindred with apoE-Philadelphia has type III hyperlipoproteinemia. Structural analysis revealed that the apoE variant had two mutations including substitutions of an arginine for cysteine at residue 145 and a lysine to glutamic acid at residue 13. Kinetic studies have established that the apoE Philadelphia variant was markedly delayed in its catabolism consistent with the clinical type III phenotype.
