Cell lipid metabolism modulators 2-bromopalmitate, D609, monensin, U18666A and probucol shift discoidal HDL formation to the smaller-sized particles: implications for the mechanism of HDL assembly

• Published in: Biochimica et biophysica acta Vol. 1861; no. 12; pp. 1968 - 1979
• Main Authors: Quach, Duyen, Vitali, Cecilia, La, Fiona M., Xiao, Angel X., Millar, John S., Tang, Chongren, Rader, Daniel J., Phillips, Michael C., Lyssenko, Nicholas N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2016
• Subjects: Androstenes - pharmacology; Animals; Apolipoprotein A-I - metabolism; ATP Binding Cassette Transporter 1 - metabolism; Bridged-Ring Compounds - pharmacology; Cell Line; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cholesterol - metabolism; Fatty Acids, Unsaturated - metabolism; HDL heterogeneity; Humans; Inhibitors of ABCA1-mediated cholesterol efflux; Lipid Metabolism - drug effects; Lipoproteins, HDL - metabolism; Macrophages - metabolism; Mechanism of HDL formation; Mice; Monensin - pharmacology; Palmitates - pharmacology; Particle Size; Phospholipids - metabolism; Probucol - pharmacology; RAW 264.7 Cells; Reconstituted HDL; Tangier disease mutations; Thiones - pharmacology; AA; ABCA1; 2BP; Inhibitors of ABCA1-mediated cholesterol efflux; Tangier disease mutations; DMSO; DTT; rHDL; choline-PL; Mechanism of HDL formation; WGA; Reconstituted HDL; MFP; apo A-I; HDL heterogeneity
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2016.09.017

ATP-binding cassette transporter A1 (ABCA1) mediates formation of disc-shaped high-density lipoprotein (HDL) from cell lipid and lipid-free apolipoprotein A-I (apo A-I). Discoidal HDL particles are heterogeneous in physicochemical characteristics for reasons that are understood incompletely. Discoidal lipoprotein particles similar in characteristics and heterogeneity to cell-formed discoidal HDL can be reconstituted from purified lipids and apo A-I by cell-free, physicochemical methods. The heterogeneity of reconstituted HDL (rHDL) is sensitive to the lipid composition of the starting lipid/apo A-I mixture. To determine whether the heterogeneity of cell-formed HDL is similarly sensitive to changes in cell lipids, we investigated four compounds that have well-established effects on cell lipid metabolism and ABCA1-mediated cell cholesterol efflux. 2-Bromopalmitate, D609, monensin and U18666A decreased formation of the larger-sized, but dramatically increased formation of the smaller-sized HDL. 2-Bromopalmitate did not appear to affect ABCA1 activity, subcellular localization or oligomerization, but induced dissolution of the cholesterol-phospholipid complexes in the plasma membrane. Arachidonic and linoleic acids shifted HDL formation to the smaller-sized species. Tangier disease mutations and inhibitors of ABCA1 activity wheat germ agglutinin and AG 490 reduced formation of both larger-sized and smaller-sized HDL. The effect of probucol was similar to the effect of 2-bromopalmitate. Taking rHDL formation as a paradigm, we propose that ABCA1 mutations and activity inhibitors reduce the amount of cell lipid available for HDL formation, and the compounds in the 2-bromopalmitate group and the polyunsaturated fatty acids change cell lipid composition from one that favors formation of the larger-sized HDL particles to one that favors formation of the smaller-sized species. •2-Bromopalmitate, D609, monensin, U18666A and probucol shift discoidal HDL formation from the larger-sized to the smaller-sized species.•Tangier disease mutations and inhibitors of ABCA1 activity wheat germ agglutinin and AG 490 reduce formation of both larger-sized and smaller-sized HDL.•Evidence is presented that the compounds in the 2-bromopalmitate group change cell lipid composition from one that favors formation of the larger-sized HDL particles to one that favors formation of the smaller-sized species.•Reconstitution HDL formation is advanced as a paradigm for the formation of discoidal HDL.