INCREASED ACTIVITY OF PLATELET-ACTIVATING-FACTOR ACETYLHYDROLASE IN LOW-DENSITY-LIPOPROTEIN SUBFRACTIONS INDUCES ENHANCED LYSOPHOSPHATIDYLCHOLINE PRODUCTION DURING OXIDATION IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Patients with heterozygous familial hypercholesterolaemia (FH) have el evated plasma concentrations of low-density lipoprotein (LDL) and deve lop premature atherosclerosis. There is increasing evidence that oxida tive modification of LDL is important for the pathogenesis of atherosc lerosis, and the LDL-associated platelet-activating factor acetylhydro lase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and hig h-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH an d 13 normolipidaemic control subjects. We also determined the lyse-PC production in each LDL subfraction during Cu2+-induced oxidation in vi tro. The total serum PAF-AH activity in heterozygous FH patients was s ignificantly higher than in control subjects, whereas the HDL-associat ed PAF-AH activity, expressed as a percentage of total serum PAF-AH ac tivity, was significantly lower in the FH patients than in control sub jects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subf ractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg(-1) protein min(-1), was signif icantly higher in the LDL3 subfraction (3.31 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respec tively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/ - 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the hete rozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No di fference was observed in the susceptibility to oxidation of each LDL s ubfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whe reas the lyse-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfra ction of the FH patients 3 h after the onset of the oxidation was sign ificantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0 .03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.0 6, respectively, for LDL3 (P < 0.02)]. Our results show that heterozyg ous FH patients exhibit higher PAF-AH activity than control subjects i n all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological poten cy. This phenomenon, in combination with the diminished anti-atherogen ic and antioxidant capability of HDL in these patients due to the rela tively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of corona ry artery disease observed in FH patients.