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.
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.
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Duyen
D
Quach
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Cecilia
C
Vitali
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Fiona M
FM
La
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Angel X
AX
Xiao
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
John S
JS
Millar
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA.
Chongren
C
Tang
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Daniel J
DJ
Rader
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Michael C
MC
Phillips
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: nilys@upenn.edu.
Nicholas N
NN
Lyssenko
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008985:Monensin / Q000494:pharmacology*; D009636:Norbornanes; D010168:Palmitates / Q000494:pharmacology*; D010316:Particle Size; D010743:Phospholipids / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*
D064286:ATP Binding Cassette Transporter 1; D000736:Androstenes; D016632:Apolipoprotein A-I; D001952:Bridged-Ring Compounds; D005231:Fatty Acids, Unsaturated; D008075:Lipoproteins, HDL; D009636:Norbornanes; D010168:Palmitates; D010743:Phospholipids; D013859:Thiocarbamates; D013871:Thiones; C022776:2-bromopalmitate; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; C046498:tricyclodecane-9-yl-xanthogenate; D008985:Monensin; D002784:Cholesterol; D011341:Probucol
HDL heterogeneity; Inhibitors of ABCA1-mediated cholesterol efflux; Mechanism of HDL formation; Reconstituted HDL; Tangier disease mutations