Pravastatin Modulates Cholesteryl Ester Transfer From HDL to ApoB-Containing Lipoproteins and Lipoprotein Subspecies Profile in Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) results from genetic defects in the LDL receptor, and is characterized by a marked elevation in plasma LDL and by qualitative abnormalities in LDL particles. Because LDL particles are major acceptors of cholesteryl esters (CEs) from HDL, significant changes occur in the flux of CE through the reverse cholesterol pathway. To evaluate the effects of an HMG-CoA reductase inhibitor, pravastatin, on CE transfer from HDL to apo B-containing lipoproteins and on plasma lipoprotein subspecies profile in subjects with heterozygous FH, we investigated the transfer of HDL-CE to LDL subfractions and changes in both concentration and chemical composition of the apo B- and the apo AI-containing lipoproteins. After pravastatin treatment (40 mg/d) for a 12-week period, plasma LDL concentrations (mean +/- SD, 745.4 +/- 51.9 mg/dL) were reduced by 36% in patients with FH (n = 6). By contrast, the qualitative features of the density profile of LDL subspecies 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 significantly increased relative to a control group, were not modified by pravastatin. In addition, no significant effect on the chemical composition of individual LDL subfractions was observed. Furthermore, plasma HDL concentrations were not modified, although the density distribution of HDL was normalized. Indeed, the HDL density peak was shifted towards the HDL2 subfraction (ratios of HDL2 to HDL3 were 0.7 and 1.1 before and after treatment, respectively). Evaluation of plasma CE transfer protein (CETP) mass was performed with an exogenous CE transfer assay. Under these conditions, no modification of plasma CETP protein mass was induced by pravastatin administration. However, the rate of CE transfer from HDL to LDL was reduced by 24% by pravastatin (61 +/- 17 micrograms 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 plasma 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-containing lipoproteins in subjects with heterozygous FH as a result of a reduction in the LDL particle acceptor concentration.

Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size

“…Figure 5 shows the model fi t of patient 20 and simulated defects affecting ApoB-mediated uptake and LPL lipolysis affi nity. The cholesterol and triglyceride concentrations in different size classes for the simulated ApoB-mediated uptake reduction show the expected hypercholesterolemia ( 49 ). The halved ApoB-related uptake affi nity results in a 1.7-fold increase of the LDL-cholesterol concentration in plasma.…”

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

“…In homozygous FH, the deleterious influence of altered apoA-I metabolism on HDL-C levels is further aggravated by decreased rates of apoA-I production (Schaefer et al, 1992). Moreover, elevated CETP activity due to the increased number of apoB-containing lipoproteins-mainly LDL-also contributes to depletion of CE from the plasma HDL pool in FH (Guerin et al, 1995(Guerin et al, , 2000b.…”

Unraveling the complexities of the HDL lipidome

“…In familial hypercholesterolemia, HDL levels of triglyceride are elevated and the cholesteryl ester/triglyceride ratio is reduced ( 120,121 ), refl ecting accelerated cholesteryl ester transfer from LDL and HDL to triglyceride-rich lipoproteins as a result of increased concentrations and abnormal properties of plasma VLDL1 ( 120,122,123 ). By contrast, attenuation of cholesteryl ester transfer from LDL and HDL to triglyceride-rich lipoproteins, as observed in plasma of subjects with heterozygous CETP defi ciency, results in elevated HDL cholesteryl ester content and reduced content of triglyceride ( 124 ).…”