ABSTRACT
Title
Cholesterol Efflux Potential of Sera After Treatment with Niacin Extended-Release or Fenofibrate
Authors
E. Favari1, M. P. Adorni1, F. Zimetti1, K. Coutant2, E. J. Niesor2, R. Benghozi2 and F. Bernini1
1Dept. of Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, Italy; 2F. Hoffmann-La Roche Ltd, Basel, Switzerland
1Dept. of Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, Italy; 2F. Hoffmann-La Roche Ltd, Basel, Switzerland
Abstract
Background: Niacin and fenofibrate are to date the most effective available HDL-raising therapies. Direct comparison of the capacity of the resulting HDL to affect reverse cholesterol transport through efflux of cholesterol from peripheral cells is still lacking.
Methods: In a multicenter, randomized, open-label, cross-over study, 66 dyslipidemic patients - 24 with low HDL-C (<40 mg/dL) and 42 with normal HDL-C (40-59 mg/dL) - received 6 weeks treatment with niacin extended-release (ER) (0.5 g/d then 1 g/d) and fenofibrate (160 mg/d) with 4 weeks’ wash-out between treatments. Plasma lipid, lipoprotein, and apolipoprotein profile was assessed. Whole serum was tested for the ability to promote cholesterol efflux by passive diffusion, ATP-binding cassette transporters (ABCA1 and ABCG1), and scavenger receptor class B, type I (SR-BI) in J774 macrophages or hepatoma cells. Results were compared to a control group having HDL>70 mg/dl.
Results: HDL particle number, size and composition were similar among groups at baseline, although the concentration of large, mature HDL particles was highest in the control group. The cholesterol efflux specific pathways at baseline were: i) SR-BI-mediated cholesterol efflux in control group > normal HDL-C (P<0.0001 ) > low HDL-C (P=0.0032); ii) ABCA1-mediated cholesterol efflux in control group < normal HDL-C = low HDL (P≤0.0001); iii) efflux via passive diffusion in control group < normal HDL-C = low HDL; iv) no significant differences in ABCG1-mediated efflux were observed across the three groups.Increases in HDL-C and apolipoprotein apo-AI were similar with fenofibrate (16.0% and 7.0% respectively) and niacin ER (15.9% and 6.6% respectively). Both fenofibrate and niacin ER increased SR-BI-mediated efflux in patients with low HDL-C (+13% and +10% respectively, P<0.05). Fenofibrate decreased ABCA1-mediated cholesterol efflux in patients with low HDL-C (-27%, P<0.05). In the same patients no change in ABCA1-mediated efflux was observed with niacin ER. Both fenofibrate and niacin ER significantly decreased ABCG1-mediated cholesterol efflux in patients with low HDL-C at baseline (-11% and -16% vs baseline respectively, P<0.05 and P<0.01). Both fenofibrate and niacin ER increased cholesterol efflux via passive diffusion in patients with low HDL-C at baseline. Both treatments did not modify efflux potential in the normal HDL group.
Conclusions: Efflux mediated by SR-BI and passive diffusion is higher and ABCA1-mediated efflux is lower in patients with physiologically high levels of mature forms of HDL than in patients with normal or low HDL-C, suggesting that the quality of HDL may determine its functional ability to promote cellular cholesterol efflux. Niacin ER and fenofibrate raised HDL-C and apoA-I levels to a similar extent. Both fenofibrate and niacin ER increased SR-BI-mediated efflux and decreased or did not modify ABCA1-mediated efflux in patients with low HDL-C, suggesting that such therapies affect not only HDL quantity but also quality and functionality, resulting in cholesterol efflux similar to that observed in subjects with physiologically high HDL-C levels.
Methods: In a multicenter, randomized, open-label, cross-over study, 66 dyslipidemic patients - 24 with low HDL-C (<40 mg/dL) and 42 with normal HDL-C (40-59 mg/dL) - received 6 weeks treatment with niacin extended-release (ER) (0.5 g/d then 1 g/d) and fenofibrate (160 mg/d) with 4 weeks’ wash-out between treatments. Plasma lipid, lipoprotein, and apolipoprotein profile was assessed. Whole serum was tested for the ability to promote cholesterol efflux by passive diffusion, ATP-binding cassette transporters (ABCA1 and ABCG1), and scavenger receptor class B, type I (SR-BI) in J774 macrophages or hepatoma cells. Results were compared to a control group having HDL>70 mg/dl.
Results: HDL particle number, size and composition were similar among groups at baseline, although the concentration of large, mature HDL particles was highest in the control group. The cholesterol efflux specific pathways at baseline were: i) SR-BI-mediated cholesterol efflux in control group > normal HDL-C (P<0.0001 ) > low HDL-C (P=0.0032); ii) ABCA1-mediated cholesterol efflux in control group < normal HDL-C = low HDL (P≤0.0001); iii) efflux via passive diffusion in control group < normal HDL-C = low HDL; iv) no significant differences in ABCG1-mediated efflux were observed across the three groups.Increases in HDL-C and apolipoprotein apo-AI were similar with fenofibrate (16.0% and 7.0% respectively) and niacin ER (15.9% and 6.6% respectively). Both fenofibrate and niacin ER increased SR-BI-mediated efflux in patients with low HDL-C (+13% and +10% respectively, P<0.05). Fenofibrate decreased ABCA1-mediated cholesterol efflux in patients with low HDL-C (-27%, P<0.05). In the same patients no change in ABCA1-mediated efflux was observed with niacin ER. Both fenofibrate and niacin ER significantly decreased ABCG1-mediated cholesterol efflux in patients with low HDL-C at baseline (-11% and -16% vs baseline respectively, P<0.05 and P<0.01). Both fenofibrate and niacin ER increased cholesterol efflux via passive diffusion in patients with low HDL-C at baseline. Both treatments did not modify efflux potential in the normal HDL group.
Conclusions: Efflux mediated by SR-BI and passive diffusion is higher and ABCA1-mediated efflux is lower in patients with physiologically high levels of mature forms of HDL than in patients with normal or low HDL-C, suggesting that the quality of HDL may determine its functional ability to promote cellular cholesterol efflux. Niacin ER and fenofibrate raised HDL-C and apoA-I levels to a similar extent. Both fenofibrate and niacin ER increased SR-BI-mediated efflux and decreased or did not modify ABCA1-mediated efflux in patients with low HDL-C, suggesting that such therapies affect not only HDL quantity but also quality and functionality, resulting in cholesterol efflux similar to that observed in subjects with physiologically high HDL-C levels.