OVERPRODUCTION OF SMALL VERY-LOW-DENSITY LIPOPROTEINS (S-F-20-60) IN MODERATE HYPERCHOLESTEROLEMIA - RELATIONSHIPS BETWEEN APOLIPOPROTEIN-BKINETICS AND PLASMA-LIPOPROTEINS

An analysis of apolipoprotein (apo) B turnovers conducted in subjects with moderate hypercholesterolemia was performed to discover relations hips that may exist between apoB kinetic parameters and plasma lipid a nd lipoprotein levels. A group of 21 subjects with plasma cholesterol in the range 250-300 mg/dl and triglyceride < 265 mg/dl were injected with tracers of I-131-labeled very low density lipoprotein 1 (VLDL(1), S-f 60-400) and I-125-labeled VLDL(2) (S-f 20-60) prepared by cumulat ive flotation ultracentrifugation. The metabolism of apoB in these fra ctions was followed through intermediate density (IDL, S-f 12-20) to l ow density (LDL, S-f 0-12) lipoprotein. The most consistent feature gi ving rise to the higher apoB levels that occurred in VLDL(2), IDL, and LDL in the hypercholesterolemic group was increased input of VLDL(2) (787 +/- 607 (SD) mg/day vs. 349 +/- 213 in normals, P < 0.01). VLDL(1 ) apoB input was variably affected and not significantly different fro m normal. However, the plasma residence time of this subfraction was i ncreased (0.15 +/- 0.07 days vs. 0.08 +/- 0.03 days in normals, P < 0. 001) due to a decreased fractional rate of direct catabolism. Fraction al transfer rates (FTR) down the delipidation cascade and other fracti onal rates of direct catabolism were, overall, not significantly diffe rent from normal. The plasma residence time of VLDL(2) apoB and LDL ap oB was similar in hypercholesterolemic and normal subjects, while that of IDL apoB was slightly increased. Variation in LDL apoB mass within the hypercholesterolemic group correlated with VLDL(1) apoB input (r = 0.58, P = 0.006), the fractional rate of transfer from IDL to LDL (r = 0.61, P = 0.003), and direct LDL input (r = 0.64, P = 0.002). The p roportion of LDL apoB mass derived by direct, i.e., VLDL-independent i nput, varied from 5 to 50% and was inversely correlated with plasma tr iglyceride (r = -0.53, P = 0.014) and positively with HDL(2) (r = 0.66 , P = 0.002). In addition, the amount of direct LDL input was related to the amount of VLDL(1) removed by direct catabolism (r = 0.53, P = 0 .013). The analysis indicated that moderate hypercholesterolemia arose principally from overproduction of small VLDL, while variation in VLD L(1) input and the IDL to LDL conversion rate (presumably hepatic lipa se-mediated) modulated the extent of the elevation in LDL apoB.