IN-VIVO METABOLISM OF APOLIPOPROTEIN A-IV IN SEVERE HYPERTRIGLYCERIDEMIA - A COMBINED RADIOTRACER AND STABLE-ISOTOPE KINETIC-STUDY

Apolipoprotein (apo) A-IV is an intestinally derived apolipoprotein th at plays a potentially important role in lipoprotein metabolism and re verse cholesterol transport. However, the factors that regulate its pl asma concentrations are not well understood. Plasma apoA-IV levels hav e been previously shown to correlate with fasting triglyceride (TG) le vels in humans with TG levels less than 300 mg/dl (Lagrost et al. 1989 . J. Lipid Res. 30: 701-710). In this study, we established that apoA- IV levels were significantly elevated (mean 29.3 mg/dl) in a group of 15 hypertriglyceridemic patients (TG > 300 mg/dl) compared with normol ipidemic controls (mean 13.4 mg/dl). In order to investigate the relat ionship between hypertriglyceridemia and apoA-IV metabolism, we then s tudied the in vivo kinetics of apoA-IV in two healthy hypertriglycerid emic patients (mean TG = 1297 mg/dl) compared with normolipidemic cont rol subjects. Combined studies using endogenous stable isotope labelin g (with a primed constant infusion of deuterated L-leucine) and exogen ous radiolabeling (with I-125) of apoA-IV were performed. Both stable isotope and radiotracer studies demonstrated substantially decreased a poA-IV fractional catabolic rates (FCR) in the hypertriglyceridemic pa tients (1.24 +/- 0.13 day(-1)) compared with controls (2.33 +/- 0.08 d ay(-1)). The apoA-IV production rate was not significantly different b etween the two groups. Gel filtration chromatography of plasma indicat ed an increased proportion of apoA-IV in the triglyceride-rich lipopro teins (TRL) of the hypertriglyceridemic patients compared with control s and delayed catabolism of this TRL-associated apoA-IV. The rate of a poA-IV catabolism from the lipid deficient fraction was not different between the hypertriglyceridemic patients and controls. In summary, pl asma levels of apoA-IV are significantly elevated in hypertriglyceride mic patients due to delayed catabolism of apoA-IV as demonstrated by b oth endogenous stable isotope labeling and exogenous radiotracer techn iques.