Macrophage cholesterol efflux to plasma and HDL in subjects with low and high homocysteine levels: a FIELD substudy

Abstract

Objectives: Increases of homocysteine (Hcy) by fenofibrate correlated inversely to changes in HDL-C and apoA-I in the FIELD study. This finding raised the question whether high Hcy may influence HDL function and counteract benefits of fenofibrate on cardiovascular outcomes. In a subset of the FIELD study we investigated whether fenofibrate therapy or high Hcy, separately or in concert, modulate: (1) ability of plasma or HDL to facilitate cholesterol efflux from THP-1 foam cells; (2) plasma potential to generate preβ-HDL; (3) plasma phospholipid transfer protein (PLTP) activity, serum PON-1 mass and activity, HDL particle size and distribution.

Methods: We selected 33 subjects in the FIELD fenofibrate arm according to quartiles of Hcy at 5th year: 17 subjects were in the lowest (Low Hcy group) and 16 subjects were in the highest quartile (High Hcy group). In addition, 14 subjects allocated to placebo were matched by close-out Hcy levels to Low Hcy group. This design allowed us to examine the effects of both fenofibrate (comparison between placebo vs Low Hcy groups) and Hcy (comparison between close-out Low and High Hcy groups) on plasma and HDL ability to facilitate cellular cholesterol removal in the efflux assay in vitro using THP-1 foam cells.

Results: Hcy levels were 13.3±0.7 μmol/L (placebo), 13.2±2 μmol/L (Low Hcy) and 27.4±6.5 μmol/L (High Hcy). Cholesterol efflux values to HDL and plasma, percentage of plasma preβ-HDL, PLTP activity, serum PON-1 mass and HDL particle size and distribution were similar in both fenofibrate groups and comparable to those of the placebo group.

Conclusions: In the present study cohort fenofibrate and high Hcy levels did not modulate HDL and plasma functions in the first step of reverse cholesterol transport, cholesterol efflux from foam cells.