The polar nature of 7-ketocholesterol determines its location within membrane domains and the kinetics of membrane microsolubilization by apolipoprotein A-I.
7-Ketocholesterol is an oxidized derivative of cholesterol with numerous physiological effects. In model membranes, 7-ketocholesterol and cholesterol were compared by physical measures of bilayer order and polarity, formation of detergent resistant domains (DRM), phase separation, and membrane microsolubilization by apolipoprotein A-I. In binary mixtures of a saturated phosphatidylcholine (PC), dipalmitoyl-PC (DPPC), and cholesterol or 7-ketocholesterol, the sterols modulate bilayer order and polarity and induce DRM formation to a similar extent. Cholesterol induces formation of ordered lipid domains (rafts) in tertiary mixtures with dioleoyl-PC (DOPC) and DPPC, or DOPC and sphingomyelin (SM). In tertiary mixtures, cholesterol increased lipid order and reduces bilayer polarity more than 7-ketocholesterol. This effect was more pronounced when the mixtures were in a miscible liquid-disordered (L(d)) phase. Substitution of 7-ketocholesterol for cholesterol dramatically reduced the extent of DRM formation in DOPC/DPPC and DOPC/SM bilayers and ordered lipid phase separation in mixtures of a spin-labeled PC with DPPC and with SM. Compared to cholesterol, 7-ketocholesterol decreased the rate for the microsolubilization of dimyristoyl-PC multilamellar vesicles by apolipoprotein A-I. The membrane effects of 7-ketocholesterol were dependent on the phospholipid matrix. In L(d) phase phospholipids, a model for 7-ketocholesterol indicates that the proximity of the 7-keto and 3beta-OH groups puts both polar moieties at the lipid-water interface to tilt the sterol nucleus to the plane of the bilayer. 7-Ketocholesterol was less effective in forming ordered lipid domains, in decreasing the level of bilayer hydration, and in forming phase boundary bilayer defects. Compared to cholesterol, 7-ketocholesterol can differentially modulate membrane properties involved in protein-membrane association and function.
Massey
John B
JB
Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. jbm@bcm.tmc.edu
Pownall
Henry J
HJ
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000737:chemistry*; D008076:Cholesterol, HDL / Q000737:chemistry; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D006801:Humans; D007653:Ketocholesterols / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism; D017830:Octoxynol; D044367:Phase Transition; D010713:Phosphatidylcholines / Q000737:chemistry; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013109:Sphingomyelins / Q000737:chemistry
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007653:Ketocholesterols; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D015060:1,2-Dipalmitoylphosphatidylcholine; D017830:Octoxynol; C017251:1,2-oleoylphosphatidylcholine; C003001:7-ketocholesterol; D004134:Dimyristoylphosphatidylcholine