Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer. In this study, the effects of oxidative stress on membrane phospholipid and sterol organization were measured using small angle x-ray diffraction approaches. Model membranes enriched in dilinoleoylphosphatidylcholine were prepared at various concentrations of cholesterol and subjected to lipid peroxidation at physiologic conditions. At cholesterol-to-phospholipid mole ratios (C/P) as low as 0.4, lipid peroxidation induced the formation of discrete, membrane-restricted cholesterol domains having a unit cell periodicity or d-space value of 34 Å. The formation of cholesterol domains correlated directly with lipid hydroperoxide levels and was inhibited by treatment with vitamin E. In the absence of oxidative stress, similar cholesterol domains were observed only at C/P ratios of 1.0 or higher. In addition to changes in sterol organization, lipid peroxidation also caused reproducible changes in overall membrane structure, including a 10 Å reduction in the width of the surrounding, sterol-poor membrane bilayer. These data provided direct evidence that lipid peroxidation alters the essential organization and structure of membrane lipids in a manner that may contribute to changes in membrane function during aging and oxidative stress-related disorders. Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer. In this study, the effects of oxidative stress on membrane phospholipid and sterol organization were measured using small angle x-ray diffraction approaches. Model membranes enriched in dilinoleoylphosphatidylcholine were prepared at various concentrations of cholesterol and subjected to lipid peroxidation at physiologic conditions. At cholesterol-to-phospholipid mole ratios (C/P) as low as 0.4, lipid peroxidation induced the formation of discrete, membrane-restricted cholesterol domains having a unit cell periodicity or d-space value of 34 Å. The formation of cholesterol domains correlated directly with lipid hydroperoxide levels and was inhibited by treatment with vitamin E. In the absence of oxidative stress, similar cholesterol domains were observed only at C/P ratios of 1.0 or higher. In addition to changes in sterol organization, lipid peroxidation also caused reproducible changes in overall membrane structure, including a 10 Å reduction in the width of the surrounding, sterol-poor membrane bilayer. These data provided direct evidence that lipid peroxidation alters the essential organization and structure of membrane lipids in a manner that may contribute to changes in membrane function during aging and oxidative stress-related disorders. Lipid peroxidation is a degenerative process that affects unsaturated membrane lipids under conditions of oxidative stress (1Girotti A.W. J. Lipid Res. 1998; 39: 1529-1542Abstract Full Text Full Text PDF PubMed Google Scholar). This complex process is believed to contribute to human aging and disease by disrupting the structural conformation, the packing of lipid components and, ultimately, the function of biological membranes. The polyunsaturated fatty acids of membrane phospholipids are particularly susceptible to peroxidation and undergo significant modifications, including the rearrangement or loss of double bonds and, in some cases, the reductive degradation of lipid acyl side chains (2Leibowitz M.E. Johnson M.C. J. Lipid Res. 1971; 12: 662-670Abstract Full Text PDF PubMed Google Scholar, 3Gardner H.W. J. Agric. Food Chem. 1975; 23: 129-136Crossref PubMed Scopus (212) Google Scholar, 4Buege J.A. Aust S.D. Methods Enzymol. 1978; 52: 302-310Crossref PubMed Scopus (10916) Google Scholar). Lipid hydroperoxides, prominent intermediates of peroxidative reactions, also accumulate in the bilayer and further contribute to changes in the structural organization and packing of membrane lipid components (1Girotti A.W. J. Lipid Res. 1998; 39: 1529-1542Abstract Full Text Full Text PDF PubMed Google Scholar). Many of the biophysical consequences of these structural modifications have been well characterized and include changes in membrane fluidity (5Petrescu A.D. Gallegos A.M. Okamura Y. Strauss III, J.F. Schroeder F. J. Biol. Chem. 2001; 276: 36970-36982Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 6Chatterjee S.N. Agarwal S. Free Radic. Biol. Med. 1988; 4: 51-72Crossref PubMed Scopus (236) Google Scholar, 7Borchman D. Lamba O.P. Salmassi S. Lou M. Yappert M.C. Lipids. 1992; 27: 261-265Crossref PubMed Scopus (56) Google Scholar), increased membrane permeability (6Chatterjee S.N. Agarwal S. Free Radic. Biol. Med. 1988; 4: 51-72Crossref PubMed Scopus (236) Google Scholar, 8Goldstein R.M. Weissmann G. Biochem. Biophys. Res. Commun. 1977; 75: 604-609Crossref PubMed Scopus (63) Google Scholar, 9Mandal T.K. Chatterjee S.N. Radiat. Res. 1980; 83: 290-302Crossref PubMed Scopus (80) Google Scholar, 10Kunimoto M. Inoue K. Nojima S. Biochim. Biophys. 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Physiol. 1998; 275: C1-C24Crossref PubMed Google Scholar, 18Mattson M.P. Trends Neurosci. 1998; 21: 53-57Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 19Mattson M.P. Pedersen W.A. Duan W. Culmsee C. Camandola S. Ann. N. Y. Acad. Sci. 1999; 893: 154-175Crossref PubMed Scopus (306) Google Scholar, 20Sevanian A. Ursini F. Free Radic. Biol. Med. 2000; 29: 306-311Crossref PubMed Scopus (129) Google Scholar). Recent studies conducted in our laboratory have provided direct evidence for changes in the molecular organization of membrane lipid bilayers following exposure to oxidative stress. Using small angle x-ray diffraction approaches, we examined model membranes composed of dilinoleoylphosphatidylcholine (DLPC) 2The abbreviations used are:DLPCdilinoleoylphosphatidylcholine (1,2-dilinoleoyl-3-sn-phosphatidylcholine)POPCpalmitoylphosphatidylcholine (1-palmitoyl,2-oleoyl-3-sn-phosphatidylcholine)C/Pcholesterol-to-phospholipid , before and after exposure to oxidative stress (21Mason R.P. Walter M.F. Mason P.E. Free Radic. Biol. Med. 1997; 23: 419-425Crossref PubMed Scopus (99) Google Scholar). Moderate levels of lipid peroxidation produced significant and reproducible alterations in the basic structure of the membrane phospholipid bilayer, including a marked reduction in membrane d-space (i.e. bilayer width plus surface hydration) and a decrease in intrabilayer headgroup separation. In addition, lipid peroxidation promoted an increase in the molecular volume associated with the unsaturated region of the hydrocarbon core and induced the apparent interdigitation of the phospholipid acyl chain terminal methyl segments (21Mason R.P. Walter M.F. Mason P.E. Free Radic. Biol. Med. 1997; 23: 419-425Crossref PubMed Scopus (99) Google Scholar). Similar changes in membrane bilayer structure have also been observed in membranes reconstituted from cardiac phospholipids (21Mason R.P. Walter M.F. Mason P.E. Free Radic. Biol. Med. 1997; 23: 419-425Crossref PubMed Scopus (99) Google Scholar) and in DLPC-enriched model membranes exposed to autoxidative forms of lipid peroxidation (22Mason R.P. Jacob R.F. Methods Mol. Biol. 2002; 196: 69-78PubMed Google Scholar). dilinoleoylphosphatidylcholine (1,2-dilinoleoyl-3-sn-phosphatidylcholine) palmitoylphosphatidylcholine (1-palmitoyl,2-oleoyl-3-sn-phosphatidylcholine) cholesterol-to-phospholipid In this report, we extended this line of investigation by measuring the effects of lipid peroxidation on cholesterol organization and distribution in model membrane bilayers. Perturbation of membrane cholesterol content and structural organization has been implicated in the pathogenesis of a number of human diseases, many of which are also linked to conditions of increased oxidative stress. Numerous studies have shown that cholesterol directly modulates the physical properties of lipid bilayers, altering membrane responses to degenerative processes, including lipid peroxidation (23McLean L.R. Hagaman K.A. Free Radic. Biol. Med. 1992; 12: 113-119Crossref PubMed Scopus (77) Google Scholar, 24Leonard A. Dufourc E.J. Biochimie (Paris). 1991; 73: 1295-1302Crossref PubMed Scopus (51) Google Scholar, 25Mowri H. Nojima S. Inoue K. J. Biochem. (Tokyo). 1984; 95: 551-558Crossref PubMed Scopus (71) Google Scholar); however, little is known about the consequences of such processes on the membrane properties of cholesterol itself. In this study, small angle x-ray diffraction approaches were used to directly characterize the distribution of cholesterol in DLPC-enriched membranes exposed to various levels of peroxidative stress. The results of these experiments demonstrated that lipid peroxidation of membranes containing low levels of cholesterol (cholesterol-to-phospholipid mole ratios ranging between 0.4 and 0.8) promotes the formation of immiscible, membrane-restricted cholesterol domains. The formation of cholesterol domains was highly dependent on the extent of lipid peroxidation and was significantly inhibited by the addition of vitamin E. These data provided direct evidence for membrane lipid reorganization following oxidative insult and further implicated lipid peroxidation as an important contributor to mechanisms of aging and disease. Materials—DLPC and 1-palmitoyl,2-oleoyl-3-sn-phosphatidylcholine (POPC) were obtained from Avanti Polar Lipids (Alabaster, AL) and in at was also from Avanti Polar Lipids and in at was prepared to a from M. H. M. M. G. J. Lipid Res. Full Text PDF PubMed Google Scholar) and of 10 and to the was by and was prepared in to and with lipids during membrane of of with cholesterol-to-phospholipid (C/P) mole ratios ranging from to were prepared as lipids were to and under a of was by for a of under membrane was in diffraction to a phospholipid of 1.0 were by for at A.D. J. Mol. Biol. PubMed Scopus Google Scholar). composed of and cholesterol were also prepared using this after of membrane were for peroxidation and diffraction as Lipid lipid membrane were subjected to by at in an of were at and with 1.0 of the for of lipid formation were for of peroxidation and between and 10 were with and at for in the absence of were measured a at using a The is on the of by lipid and to the following The of in this is directly to the of lipid in the membrane The value of is at M. H. M. M. G. J. Lipid Res. Full Text PDF PubMed Google Scholar). of for were for x-ray diffraction as S. D. Biophys. J. Full Text PDF Scopus Google Scholar). containing of on were to containing an which to a membrane were a and at that were to of peroxidation were for that peroxidation the were and the the membrane were from the and The were in in which and were during x-ray diffraction was used to a of in these and were at this at to membrane were at with to a x-ray produced by a The are by of a and are a to and of the x-ray was using a data were on a x-ray using a of In addition to direct cholesterol was used to the of the This for of the unit cell or of the membrane lipid bilayer, which is the from the of lipid bilayer to the including surface The d-space for membrane is from is the diffraction is the of the x-ray is the membrane lipid bilayer unit cell and is the angle to the angle between the and of on Lipid membranes composed of cholesterol a C/P mole of or cholesterol the C/P mole were prepared and subjected to by at for Lipid peroxidation was at from using the In the absence of peroxidation was observed to increase by between to the of lipid increased by at The addition of cholesterol to membranes in lipid hydroperoxide levels at that were observed for with a increase at the significant changes in lipid levels were observed between peroxidation data as has been shown for (21Mason R.P. Walter M.F. Mason P.E. Free Radic. Biol. Med. 1997; 23: 419-425Crossref PubMed Scopus (99) Google Scholar), that significantly alters membrane structure, and such changes particularly in the of This was in this using small angle x-ray diffraction approaches. diffraction from and cholesterol at and peroxidation are shown in data from the diffraction and a unit cell periodicity of Å the lipid diffraction was and the membrane d-space was to Å with a membrane The addition of cholesterol to bilayers at peroxidation in an increase in membrane periodicity to Å of membrane phospholipid periodicity to Å in the of cholesterol The diffraction from this also the of prominent cholesterol as by well having a unit cell periodicity of 34 Å. These data that lipid peroxidation significant changes in membrane structure, the of which is the phase of cholesterol membrane domains. This lipid was observed in membranes containing concentrations of cholesterol and exposed to the of oxidative stress and of and on the basic biophysical for the formation of cholesterol domains as observed in these model x-ray diffraction approaches were used to membrane containing cholesterol at C/P mole ratios ranging from to 1.0 At peroxidation cholesterol formation was observed at C/P mole ratios 1.0 that cholesterol content is for phase to under conditions. in bilayer packing and distribution of cholesterol are particularly well in the C/P mole the phospholipid diffraction prominent in the absence of cholesterol at This is with an increased packing of cholesterol the hydrocarbon core of the phospholipid bilayer R.P. Mol. 1992; Google Scholar, Biochim. Biophys. 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Lipid peroxidation significantly the cholesterol packing effects observed in membranes at of well diffraction to cholesterol domains were apparent at C/P mole ratios as low as 0.4 The associated with the phospholipid diffraction at C/P that cholesterol formation may induced at this cholesterol cholesterol were obtained at This of experiments that a C/P of was for cholesterol formation in in further characterize the effects of peroxidation on cholesterol composed of cholesterol at C/P were prepared and examined at a lipid peroxidation well diffraction associated with cholesterol domains were as as and further peroxidation promoted the formation of cholesterol diffraction cholesterol were from the of the cholesterol for and the of peroxidation that the of the 34 Å cholesterol also increased as a function of exposure to oxidative insult however, the cholesterol with the or phospholipid diffraction the Å were for was using a for These data that cholesterol increased in a with a function that is similar to the changes in lipid formation of lipid peroxidation on cholesterol was on the of the Å observed in the diffraction obtained from and that cholesterol increased at in with increased lipid formation as in the with these changes in cholesterol structural organization, lipid peroxidation also induced significant changes in the structural organization of the phospholipid bilayer. shown in the membrane d-space of with of peroxidation of the membrane periodicity obtained from membranes are also in to cholesterol to increase membrane structural as by the d-space associated with and however, this was at with in lipid and cholesterol formation of on treatment of model membranes with vitamin vitamin to phospholipid mole the formation of cholesterol domains to the peroxidation this vitamin inhibited lipid formation by In x-ray diffraction vitamin was shown to have effects on the structural organization of cholesterol domains in membranes with cholesterol C/P mole These data that vitamin as a function of significantly alteration of membrane structure and cholesterol Lipid peroxidation is a that affects polyunsaturated fatty acids in biological membranes. 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