Fenofibrate Reduces Plasma Cholesteryl Ester Transfer From HDL to VLDL and Normalizes the Atherogenic, Dense LDL Profile in Combined Hyperlipidemia

Abstract

The effect of fenofibrate on plasma cholesteryl ester transfer protein (CETP) activity in relation to the quantitative and qualitative features of apoB- and apoA-I-containing lipoprotein subspecies was investigated in nine patients presenting with combined hyperlipidemia. Fenofibrate (200 mg/d for 8 weeks) induced significant reductions in plasma cholesterol (-16%; P < .01), triglyceride (-44%; P < .007), VLDL cholesterol (-52%; P = .01), LDL cholesterol (-14%; P < .001), and apoB (-15%; P < .009) levels and increased HDL cholesterol (19%; P = .0001) and apoA-I (12%; P = .003) levels. An exogenous cholesteryl ester transfer (CET) assay revealed a marked decrease (-26%; P < .002) in total plasma CETP-dependent CET activity after fenofibrate treatment. Concomitant with the pronounced reduction in VLDL levels (37%; P < .005), the rate of CET from HDL to VLDL was significantly reduced by 38% (P = .0001), whereas no modification in the rate of cholesteryl ester exchange between HDL and LDL occurred after fenofibrate therapy. Combined hyperlipidemia is characterized by an asymmetrical LDL profile in which small, dense LDL subspecies (LDL-4 and LDL-5, d = 1.039 to 1.063 g/mL) predominate. Fenofibrate quantitatively normalized the atherogenic LDL profile by reducing levels of dense LDL subspecies (-21%) and by inducing an elevation (26%; P < .05) in LDL subspecies of intermediate density (LDL-3, d = 1.029 to 1.039 g/mL), which possess optimal binding affinity for the cellular LDL receptor. However, no marked qualitative modifications in the chemical composition or size of LDL particles were observed after drug treatment. Interestingly, the HDL cholesterol concentration was increased by fenofibrate therapy, whereas no significant change was detected in total plasma HDL mass. In contrast, the HDL subspecies pattern was modified as the result of an increase in the total mass (11.7%) of HDL2a, HDL3a, and HDL3b (d = 1.091 to 1.156 g/mL) at the expense of reductions in the total mass (-23%) of HDL2b (d = 1.063 to 1.091 g/mL) and HDL3c (d = 1.156 to 1.179 g/mL). Such changes are consistent with a drug-induced reduction in CETP activity. In conclusion, the overall mechanism involved in the fenofibrate-induced modulation of the atherogenic dense LDL profile in combined hyperlipidemia primarily involves reduction in CET from HDL to VLDL together with normalization of the intravascular transformation of VLDL precursors to receptor-active LDLs of intermediate density.

Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome

“…The lack of effect of fenofibrate on CETP activity compared with atorvastatin could be related to increased transport rate of LDL apoB and the unchanged pool size of the corresponding cholesterol acceptor lipoprotein. Fibrates have not been shown consistently to decrease CETP activity (48,49). Hence, in our study the increase in plasma HDL cholesterol and apoAI concentrations with fenofibrate could be attributable chiefly to the increase in apoAI synthesis, given also the unaltered plasma LCAT activity and the significant increase in FCR of apoAI.…”

Fenofibrate Effectively Reduces Remnants, and Small Dense LDL, and Increases HDL Particle Number in Hypertriglyceridemic Men &mdash; A Nuclear Magnetic Resonance Study

“…Several studies have focused on the effects of fenofibrate on li-indicate that increased HDL-C by fenofibrate is likely due to an increased production of apoA-I (31,32), together with decreased cholesteryl ester transfer protein activity (19) and increased ABCA1 (33). Overall, its observed alteration of HDL makes fenofibrate an ideal agent for strengthening the anti-atherogenic properties of HDL, when used in hypertriglyceridemic patients.…”

Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

“…Although the lipid content of the lipoprotein particles was not measured, these data are consistent with inhibition of the triglyceridemediated lipid exchange between VLDL and LDL particles. In combined hyperlipidemic subjects, fenofibrate (200 mg/day for 8 weeks) reduced cholesteryl ester transfer protein-mediated cholesteryl ester transfer from HDL to VLDL, inducing a shift from dense LDL to intermediatedense LDL subspecies (26).…”