Probucol Treatment is Associated with an ABCA1-independent Mechanism of Cholesterol Efflux to Lipid Poor Apolipoproteins from Foam Cell Macrophages

Overview

Journal BBA Adv

Specialty Biochemistry

Date 2023 Apr 21

PMID 37082009

Authors

Anouar Hafiane

Alessandro Pisaturo

Annalisa Ronca

Matteo Incerti

Robert S Kiss

Elda Favari

Affiliations

Soon will be listed here.

Abstract

Objective: Probucol is a cholesterol-lowering agent whose ability to prevent atherosclerosis is currently under study. Herein, we investigate the putative mechanism of probucol by observation of changes in cellular cholesterol efflux and lipid droplet morphology in macrophages.

Results: The inhibitory activity of probucol was assessed in non-foam or foam cell macrophages expressing ABCA1 generated by treatment with fetal calf serum (FCS) alone or in combination with acetylated LDL, respectively. Probucol inhibited cholesterol efflux to apolipoprotein A-I (apoA-I) by 31.5±0.1% in THP-1 non-foam cells and by 18.5±0.2% in foam cells. In probucol-treated non-foam THP-1 cells, nascent high density lipoprotein (nHDL) particles with a diameter < 7 nm were generated, while in probucol-treated THP-1 foam cells nHDL particles of > 7 nm in diameter containing cholesterol were produced. Foam cells also displayed a significant accumulation of free cholesterol at the plasma membrane, as measured by percent cholestenone formed. Intracellularly, there was a significant decrease in lipid droplet number and an increase in size in probucol-treated THP-1 foam cells when compared to non-treated cells.

Conclusions: We report for the first time that probucol is unable to completely inhibit cholesterol efflux in foam cells to the same extent as in non-foam cells. Indeed, functional nHDL is released from foam cells in the presence of probucol. This difference in inhibitory effect could potentially be explained by changes in the plasma membrane pool as well as intracellular cholesterol storage independently of ABCA1.

Citing Articles

High Density Lipoprotein-Based Therapeutics: Novel Mechanism of Probucol in Foam Cells.

Hafiane A, Ronca A, Kiss R, Favari E Front Cardiovasc Med. 2022; 9:895031.

PMID: 35557540 PMC: 9086955. DOI: 10.3389/fcvm.2022.895031.

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