Action of Ciprofibrate in Type IIB Hyperlipoproteinemia: Modulation of the Atherogenic Lipoprotein Phenotype and Stimulation of High-Density Lipoprotein-Mediated Cellular Cholesterol Efflux

Abstract

The effects of ciprofibrate (100 mg/d) on apolipoprotein (apo)B- and apoAI-containing lipoprotein subclasses, cholesteryl ester (CE) transfer protein activity, and plasma high-density lipoprotein (HDL)-mediated cellular cholesterol efflux were evaluated in 10 patients displaying type IIB hyperlipidemia. Plasma concentrations of large very low-density lipoprotein (VLDL)-1 (Sf 60-400) and of small VLDL-2 (Sf 20-60) were markedly diminished after fibrate treatment (-40%, P = 0.001; and -25%, P = 0.003, respectively). We observed a reduction (-17%; P = 0.005) in plasma low-density lipoprotein (LDL) levels resulting from significant reductions in concentrations of dense LDL particles (-46%; P < 0.0001). Ciprofibrate induced elevation in plasma total HDL (+13%; P = 0.005) levels; such elevation occurred preferentially in HDL-3 (+22%; P = 0.009). Marked reduction in numbers of atherogenic apoB100-containing particle acceptors was associated with a 25% decrease (P < 0.02) in CE transfer protein-mediated CE transfer from HDL. Finally, a significant fibrate-mediated elevation (+13%; P = 0.01 compared with baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from scavenger receptor class B, type I-expressing Fu5AH hepatoma cells was observed. In conclusion, the action of ciprofibrate in type IIB dyslipidemia leads to preferential reduction in particle numbers of atherogenic VLDL-1, VLDL-2, and dense LDL and, concomitantly, to elevation in HDL-3 levels that are associated with stimulation of HDL-mediated cellular free cholesterol efflux through the scavenger receptor class B, type I receptor pathway.

Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression

“…HDL-cholesterol levels can theoretically be modulated by several key proteins involved in HDL metabolism, including ABCA1 (10), SR-BI (9), PLTP (11,23), apoA-I (3, 6, 48, 50, 51), and CETP (22,24,25). Therefore, we examined the potential contribution of each of these factors in the fenofibrate-induced increase of HDL-cholesterol in E3L.CETP mice.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…178 Also in the absence of statins, this subgroup appears to benefit over-proportionately from treatment with bezafibrate or gemfibrozil. 178 Treatment of patients with fenofibrate, bezafibrate, ciprofibrate, or the potent and selective PPAR-α agonist LY518674 increased the capacity of total or apoB-free plasma to release cholesterol from macrophages in some studies, [179][180][181][182][183] but not in others. 170,184 Potential reasons are differences in patient populations and cholesterol efflux assays.…”

PPARα activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes

“…The triglyceride-lowering effect of fibrates is partly explained by increased lipoprotein lipase expression (8) and downregulation of hepatic apolipoprotein C-III expression (9,10), which results in increased turnover of VLDL. In addition, fibrates have been shown to decrease the plasma concentration of atherogenic small dense LDL particles (11,12), indicating decreased hepatic triglyceride secretion, because small dense LDLs are products of triglyceride-rich VLDL (VLDL 1 ) particles (13). Indeed, fibrates have been shown to decrease VLDL triglyceride secretion in both humans and rats (14,15).…”