Apolipoprotein (apo) A-IV is associated with both triglyceride-rich lipoproteins (TRL) and high density lipoproteins (HDL). Though its precise role is poorly understood, it has been proposed to be involved in both triglyceride metabolism as well as reverse cholesterol transport. ApoA-IV is a polymorphic protein, and the molecular basis for all four major isoforms has been identified. The apoA-IV-2 isoprotein has been associated with lower triglyceride and higher HDL levels than the most common apoA-IV-l isoprotein. Both forms have been studied kinetically in several subjects, including six heterozygotes for apoA-IV-1/2 and one homozygote for apoA-IV-2/2. The apoA-IV-2 form has a significantly slower catabolic rate than the apoA-IV-l form, and in the homozygote was markedly slower. ApoA-l metabolism in the apoA-IV-2/2 homozygote was normal. This provides new insight into the mechanism of the higher HDL levels associated with apoA-IV-2. ApoA-IV plasma levels have been found to be positively associated with plasma triglyceride levels, whereas levels of apoA-l are inversely correlated. The metabolic explanation of this association was determined by studying the metabolism of apoA-IV and apoA-l in subjects with hypertriglyceridemia compared with normal subjects. Both exogenously-labeled radiotracers and endogenous labeling with stable isotopes were utilized. In the hypertriglyceridemic patients, the catabolic rate of apoA-IV was markedly delayed compared with normal, despite an increase in the rate of apoA-l catabolism. Hence, hypertriglyceridemia has opposite effects on apoA-IV and apoA-l catabolism, despite the close association of these apolipoproteins in plasma. The higher apoA-IV levels seen with higher levels of triglycerides are due to a delay in the rate of apoA-IV catabolism, rather than an increased synthetic rate of this apolipoprotein. These studies included subjects of age 20 to 55 years. Forty percent of the subjects in these studies were women. The studies included one African-American, one Hispanic, and two Asian subjects.