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 that plays a potentially important role in lipoprotein metabolism and reverse cholesterol transport. However, the factors that regulate its plasma concentrations are not well understood. Plasma apoA-IV levels have been previously shown to correlate with fasting triglyceride (TG) levels 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 normolipidemic controls (mean 13.4 mg/dl). In order to investigate the relationship between hypertriglyceridemia and apoA-IV metabolism, we then studied the in vivo kinetics of apoA-IV in two healthy hypertriglyceridemic patients (mean TG = 1297 mg/dl) compared with normolipidemic control subjects. Combined studies using endogenous stable isotope labeling (with a primed constant infusion of deuterated L-leucine) and exogenous radiolabeling (with 125I) of apoA-IV were performed. Both stable isotope and radiotracer studies demonstrated substantially decreased apoA-IV fractional catabolic rates (FCR) in the hypertriglyceridemic patients (1.24 +/- 0.13 day-1) compared with controls (2.33 +/- 0.08 day-1). The apoA-IV production rate was not significantly different between the two groups. Gel filtration chromatography of plasma indicated an increased proportion of apoA-IV in the triglyceride-rich lipoproteins (TRL) of the hypertriglyceridemic patients compared with controls and delayed catabolism of this TRL-associated apoA-IV. The rate of apoA-IV catabolism from the lipid deficient fraction was not different between the hypertriglyceridemic patients and controls. In summary, plasma levels of apoA-IV are significantly elevated in hypertriglyceridemic patients due to delayed catabolism of apoA-IV as demonstrated by both endogenous stable isotope labeling and exogenous radiotracer techniques.
Vergès
B
B
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Rader
D
D
Schaefer
J
J
Zech
L
L
Kindt
M
M
Fairwell
T
T
Gambert
P
P
Brewer
H B
HB
D001054:Apolipoproteins A / Q000378:metabolism* / Q000652:urine; D002850:Chromatography, Gel; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood*; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D007700:Kinetics; D014280:Triglycerides / Q000097:blood
D001054:Apolipoproteins A; D007457:Iodine Radioisotopes; D014280:Triglycerides; C022205:apolipoprotein A-IV