PRAVASTATIN MODULATES CHOLESTERYL ESTER TRANSFER FROM HDL TO APO-B-CONTAINING LIPOPROTEINS AND LIPOPROTEIN SUBSPECIES PROFILE IN FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia (FH) results from genetic defects in the LDL receptor, and is characterized by a marked elevation in plasma LD L and by qualitative abnormalities in LDL particles. Because LDL parti cles are major accepters of cholesteryl esters (CEs) from HDL, signifi cant changes occur in the flux of CE through the reverse cholesterol p athway. To evaluate the effects of an HMG-CoA reductase inhibitor, pra vastatin, on CE transfer from HDL to apo B-containing lipoproteins and on plasma lipoprotein subspecies profile in subjects with heterozygou s FH, we investigated the transfer of HDL-CE to LDL subfractions and c hanges in both concentration and chemical composition of the apo B- an d the apo AI-containing lipoproteins. After pravastatin treatment (40 mg/d) for a 12-week period, plasma LDL concentrations (mean +/- SD, 74 5.4 +/- 51.9 mg/dL) were reduced by 36% in patients with FH (n = 6). B y contrast, the qualitative features of the density profile of LDL sub species in patients with FH, in whom the intermediate (d = 1.029 to 1. 039 g/mL) and dense (d = 1.039 to 1.063 g/mL) subspecies were signific antly increased relative to a control group, were not modified by prav astatin. In addition, no significant effect on the chemical compositio n of individual LDL subfractions was observed. Furthermore, plasma HDL concentrations were not modified, although the density distribution o f HDL was normalized. Indeed, the HDL density peak was shifted towards the HDL(2) subfraction (ratios of HDL(2) to HDL(3) were 0.7 and 1.1 b efore and after treatment, respectively). Evaluation of plasma CE tran sfer protein (CETP) mass was performed with an exogenous CE transfer a ssay. Under these conditions, no modification of plasma CETP protein m ass was induced by pravastatin administration. However, the rate of CE transfer from HDL to LDL was reduced by 24% by pravastatin (61 +/- 17 mu g CE . h(-1). mL(-1) plasma; P < .0005), although intermediate and dense LDL subfractions again accounted for the majority (71%) of the total CE transferred to LDL. Thus, pravastatin induced reduction of pl asma CETP activity without change in the preferential targeting of the transfer of HDL-CE towards the denser LDL subfractions. In conclusion , pravastatin reduces the elevated flux of CE from HDL to apo B-contai ning lipoproteins in subjects with heterozygous FH as a result of a re duction in the LDL particle acceptor concentration.