Kinetics of chylomicron remnant clearance in normal and in hyperlipoproteinemic subjects

The kinetics of chylomicron metabolism have been studied by measuring retinyl palmitate in chylomicrons and their remnants for 10-12 hr following oral administration of vitamin A and Lipomul@ in three groups of adult male subjects: A) nor- mal plasma triglyceride levels (n = 7); B) endogenous hyper- triglyceridemia (n = 12); C) apolipoprotein E (apoE) phenotype E2/2, with Trpe 3 hyperlipoproteinemia (n = 4) or normal plasma lipids (n = 1). A multicompartmental model was developed using SAAM 27 to characterize the appearance, intravascular metabolism, and clearance from the plasma of retinyl palmitate- labeled dietary lipoproteins. The half-times for retinyl palmitate clearance from the chylomicron remnant fraction (TIlz REM- NANT) were 14.1 * 9.7 min in Group A; they were prolonged in Group B (50.7 * 20.8 min) and were extremely prolonged for Type 3 subjects in Group C (611.9 ~t 419.9 min). One subject with the apoE 2/2 phenotype and normal plasma triglycerides had a Tllz REMNANT of 66.8 min. Tll2 REMNANT was highly cor- related with fasting plasma triglycerides in Group A and B (r = 0.77, slope = 0.15), and in Group C (r = 0.97, slope = 0.85). These results support the interpretation that delayed chylomicron remnant clearance in subjects with en- dogenous hypertriglyceridemia may be largely secondary to over- production of VLDL particles, whose remnants compete with chylomicron remnants for removal by the liver via apoE receptor- mediated endocytosis. The subjects with apoE 2/2 have an addi- tional defect in the removal of chylomicron remnants presuma- bly due to the structural abnormality in their apoE.-Cortner, J. A., P. M. Coates, N-A. Le, D. R. Cryer, M. C. Ragni, A. Faulkner, and T. Langer. Kinetics of chylomicron remnant clear- ance in normal and in hyperlipoproteinemic subjects. J Lipid Res. 1987. 28: 195-206. of chylomicrons. As these lipoprotein particles undergo in- travascular metabolism, they become remnants still retain- ing the retinyl esters in their core (7, 8). These remnants are thought to be removed from the circulaton by hepatic uptake through a cell membrane receptor specific for the apolipoprotein E (apoE) of these remnant particles (9), fol- lowed by lysosomal hydrolysis of the cholesteryl esters and retinyl esters to free cholesterol and retinol, respectively. Unlike cholesterol, dietary-derived retinol cannot be recy- cled into hepatically derived very low density lipoproteins (VLDL), nor can it be synthesized de novo. Instead, it can be stored in the hepatocyte or secreted into the plasma com- plexed with retinol-binding protein for transport to peripheral target tissues (10). Hazzard and Bierman (1) described the first human studies in which vitamin A was used to label lipoproteins of dietary origin. More recently, Wilson and co-workers (2-4) and Berr and co-workers (5, 6) have used this ap- proach to investigate the metabolic fate of retinyl palmitate-labeled chylomicrons and their remnants in normal and hypertriglyceridemic human volunteers. With the use of a multicompartmental kinetic model for the analysis of data derived from a protocol in which dietary lipoproteins are endogenously labeled with retinyl palmitate, we have been able to estimate rates of clearance of chylomicrons and their remnants in subjects with nor- mal plasma lipids, endogenous hypertriglyceridemia, and Type 3 hyperlipoproteinemia.