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Cholesterol Reporter Molecules

  • Original Paper
  • Published:
Bioscience Reports

Abstract

Cholesterol is a major constituent of the membranes in most eukaryotic cells where it fulfills multiple functions. Cholesterol regulates the physical state of the phospholipid bilayer, affects the activity of several membrane proteins, and is the precursor for steroid hormones and bile acids. Cholesterol plays a crucial role in the formation of membrane microdomains such as “lipid rafts” and caveolae. However, our current understanding on the membrane organization, intracellular distribution and trafficking of cholesterol is rather poor. This is mainly due to inherent difficulties to label and track this small lipid. In this review, we describe different approaches to detect cholesterol in vitro and in vivo. Cholesterol reporter molecules can be classified in two groups: cholesterol binding molecules and cholesterol analogues. The enzyme cholesterol oxidase is used for the determination of cholesterol in serum and food. Susceptibility to cholesterol oxidase can provide information about localization, transfer kinetics, or transbilayer distribution of cholesterol in membranes and cells. The polyene filipin forms a fluorescent complex with cholesterol and is commonly used to visualize the cellular distribution of free cholesterol. Perfringolysin O, a cholesterol binding cytolysin, selectively recognizes cholesterol-rich structures. Photoreactive cholesterol probes are appropriate tools to analyze or to identify cholesterol binding proteins. Among the fluorescent cholesterol analogues one can distinguish probes with intrinsic fluorescence (e.g., dehydroergosterol) from those possessing an attached fluorophore group. We summarize and critically discuss the features of the different cholesterol reporter molecules with a special focus on recent imaging approaches.

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Abbreviations

ACAT:

Acyl-coenzyme A:cholesterol acyltransferase

22-NBD Cholesterol:

22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol

25-NBD Cholesterol:

25-[N-[(7-nitro-2-1,3-benzoxadiazol-4-yl)methyl]amino]-27-norcholesterol

BCθ-toxin:

A biotinylated and carlsberg protease-nicked derivative of perfringolysin O

Benzophenone-cholesterol:

22-(p-benzoylphenoxy)-23,24-bisnorcholan-5-en-3β-ol

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

MβCD:

Methyl-β-cyclodextrin

NMR:

Nuclear magnetic resonance

NPC:

Niemann-Pick C

References

  • Ahn KW, Sampson NS (2004) Cholesterol oxidase senses subtle changes in lipid bilayer structure. Biochemistry 43:827–836

    PubMed  CAS  Google Scholar 

  • Albert AD, Young JE, Yeagle PL (1996) Rhodopsin–cholesterol interactions in bovine rod outer segment disk membranes. Biochim Biophys Acta 1285:47–55

    PubMed  Google Scholar 

  • Alecio MR, Golan DE, Veatch WR, Rando RR (1982) Use of a fluorescent cholesterol derivative to measure lateral mobility of cholesterol in membranes. Proc Natl Acad Sci USA 79:5171–5174

    PubMed  CAS  Google Scholar 

  • Alpy F, Latchumanan VK, Kedinger V, Janoshazi A, Thiele C, Wendling C, Rio MC, Tomasetto C (2005) Functional characterization of the MENTAL domain. J Biol Chem 280:17945–17952

    PubMed  CAS  Google Scholar 

  • Atshaves BP, Starodub O, McIntosh A, Petrescu A, Roths JB, Kier AB, Schroeder F (2000) Sterol carrier protein-2 alters high density lipoprotein-mediated cholesterol efflux. J Biol Chem 275:36852–36861

    PubMed  CAS  Google Scholar 

  • Avdulov NA, Chochina SV, Igbavboa U, Warden CS, Schroeder F, Wood WG (1999) Lipid binding to sterol carrier protein-2 is inhibited by ethanol. Biochim Biophys Acta 1437:37–45

    PubMed  CAS  Google Scholar 

  • Bar LK, Chong PL, Barenholz Y, Thompson TE (1989) Spontaneous transfer between phospholipid bilayers of dehydroergosterol, a fluorescent cholesterol analog. Biochim Biophys Acta 983:109–112

    PubMed  CAS  Google Scholar 

  • Behnke O, Tranum-Jensen J, van Deurs B (1984) Filipin as a cholesterol probe. II. Filipin–cholesterol interaction in red blood cell membranes. Eur J Cell Biol 35:200–215

    PubMed  CAS  Google Scholar 

  • Bergeron RJ, Scott J (1982) Cholestatriene and ergostatetraene as in vivo and in vitro membrane and lipoprotein probes. J Lipid Res 23:391–404

    PubMed  CAS  Google Scholar 

  • Bjorkqvist YJ, Nyholm TK, Slotte JP, Ramstedt B (2005) Domain formation and stability in complex lipid bilayers as reported by cholestatrienol. Biophys J 88:4054–4063

    PubMed  Google Scholar 

  • Blanchette-Mackie EJ (2000) Intracellular cholesterol trafficking: role of the NPC1 protein. Biochim Biophys Acta 1486:171–183

    PubMed  CAS  Google Scholar 

  • Bolard J (1986) How do the polyene macrolide antibiotics affect the cellular membrane properties? Biochim Biophys Acta 864:257–304

    PubMed  CAS  Google Scholar 

  • Brasaemle DL, Robertson AD, Attie AD (1988) Transbilayer movement of cholesterol in the human erythrocyte membrane. J Lipid Res 29:481–489

    PubMed  CAS  Google Scholar 

  • Burger K (2000) Cholesterin und Progesteron – Modulatoren G-Protein gekoppelter Signaltransduktionswege. Dissertation, Mainz

  • Burger K, Gimpl G, Fahrenholz F (2000) Regulation of receptor function by cholesterol. Cell Mol Life Sci 57:1577–1592

    PubMed  CAS  Google Scholar 

  • Butler JD, Comly ME, Kruth HS, Vanier M, Filling-Katz M, Fink J, Barton N, Weintroub H, Quirk JM, Tokoro T (1987) Niemann-pick variant disorders: comparison of errors of cellular cholesterol homeostasis in group D and group C fibroblasts. Proc Natl Acad Sci USA 84:556–560

    PubMed  CAS  Google Scholar 

  • Butler JD, Blanchette-Mackie J, Goldin E, O’Neill RR, Carstea G, Roff CF, Patterson MC, Patel S, Comly ME, Cooney A (1992) Progesterone blocks cholesterol translocation from lysosomes. J Biol Chem 267:23797–23805

    PubMed  CAS  Google Scholar 

  • Cai TQ, Guo Q, Wong B, Milot D, Zhang L, Wright SD (2002) Protein-disulfide isomerase is a component of an NBD-cholesterol monomerizing protein complex from hamster small intestine. Biochim Biophys Acta 1581:100–108

    PubMed  CAS  Google Scholar 

  • Castanho MA, Coutinho A, Prieto MJ (1992) Absorption and fluorescence spectra of polyene antibiotics in the presence of cholesterol. J Biol Chem 267:204–209

    PubMed  CAS  Google Scholar 

  • Challa R, Ahuja A, Ali J, Khar RK (2005) Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech 6:E329–E357

    PubMed  Google Scholar 

  • Charrin S, Manie S, Thiele C, Billard M, Gerlier D, Boucheix C, Rubinstein E (2003) A physical and functional link between cholesterol and tetraspanins. Eur J Immunol 33:2479–2489

    PubMed  CAS  Google Scholar 

  • Chattopadhyay A (1990) Chemistry and biology of N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-labeled lipids: fluorescent probes of biological and model membranes. Chem Phys Lipids 53:1–15

    PubMed  CAS  Google Scholar 

  • Chattopadhyay A, London E (1987) Parallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids. Biochemistry 26:39–45

    PubMed  CAS  Google Scholar 

  • Chattopadhyay A, London E (1988) Spectroscopic and ionization properties of N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-labeled lipids in model membranes. Biochim Biophys Acta 938:24–34

    PubMed  CAS  Google Scholar 

  • Corbin J, Wang HH, Blanton MP (1998) Identifying the cholesterol binding domain in the nicotinic acetylcholine receptor with [125I]azido-cholesterol. Biochim Biophys Acta 1414:65–74

    PubMed  CAS  Google Scholar 

  • Cruz JC, Thomas M, Wong E, Ohgami N, Sugii S, Curphey T, Chang CC, Chang TY (2002) Synthesis and biochemical properties of a new photoactivatable cholesterol analog 7,7-azocholestanol and its linoleate ester in Chinese hamster ovary cell lines. J Lipid Res 43:1341–1347

    PubMed  CAS  Google Scholar 

  • Dagher G, Donne N, Klein C, Ferre P, Dugail I (2003) HDL-mediated cholesterol uptake and targeting to lipid droplets in adipocytes. J Lipid Res 44:1811–1820

    PubMed  CAS  Google Scholar 

  • de Kruijff B, Demel RA (1974) Polyene antibiotic-sterol interactions in membranes of Acholeplasma laidlawii cells and lecithin liposomes. 3. Molecular structure of the polyene antibiotic–cholesterol complexes. Biochim Biophys Acta 339:57–70

    PubMed  Google Scholar 

  • Devaux PF, Fellmann P, Herve P (2002) Investigation on lipid asymmetry using lipid probes: comparison between spin-labeled lipids and fluorescent lipids. Chem Phys Lipids 116:115–134

    PubMed  CAS  Google Scholar 

  • Elias PM, Friend DS, Goerke J (1979) Membrane sterol heterogeneity. Freeze-fracture detection with saponins and filipin. J Histochem Cytochem 27:1247–1260

    PubMed  CAS  Google Scholar 

  • Fernandez AM, Fernandez-Ballester G, Ferragut JA, Gonzalez-Ros JM (1993) Labeling of the nicotinic acetylcholine receptor by a photoactivatable steroid probe: effects of cholesterol and cholinergic ligands. Biochim Biophys Acta 1149:135–144

    PubMed  CAS  Google Scholar 

  • Fielding PE, Russel JS, Spencer TA, Hakamata H, Nagao K, Fielding CJ (2002) Sterol efflux to apolipoprotein A–I originates from caveolin-rich microdomains and potentiates PDGF-dependent protein kinase activity. Biochemistry 41:4929–4937

    PubMed  CAS  Google Scholar 

  • Fischer RT, Stephenson FA, Shafiee A, Schroeder F (1984) Delta 5,7,9(11)-Cholestatrien-3 beta-ol: a fluorescent cholesterol analogue. Chem Phys Lipids 36:1–14

    PubMed  CAS  Google Scholar 

  • Friedland N, Liou HL, Lobel P, Stock AM (2003) Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc Natl Acad Sci USA 100:2512–2517

    PubMed  CAS  Google Scholar 

  • Frolov A, Woodford JK, Murphy EJ, Billheimer JT, Schroeder F (1996) Spontaneous and protein-mediated sterol transfer between intracellular membranes. J Biol Chem 271:16075–16083

    PubMed  CAS  Google Scholar 

  • Frolov A, Petrescu A, Atshaves BP, So PT, Gratton E, Serrero G, Schroeder F (2000) High density lipoprotein-mediated cholesterol uptake and targeting to lipid droplets in intact L-cell fibroblasts. A single- and multiphoton fluorescence approach. J Biol Chem 275:12769–12780

    PubMed  CAS  Google Scholar 

  • Fujimoto T, Hayashi M, Iwamoto M, Ohno-Iwashita Y (1997) Crosslinked plasmalemmal cholesterol is sequestered to caveolae: analysis with a new cytochemical probe. J Histochem Cytochem 45:1197–1205

    PubMed  CAS  Google Scholar 

  • Gallegos AM, Storey SM, Kier AB, Schroeder F, Ball JM (2006) Structure and cholesterol dynamics of caveolae/raft and nonraft plasma membrane domains. Biochemistry 45:12100–12116

    PubMed  CAS  Google Scholar 

  • Ghoshroy KB, Zhu W, Sampson NS (1997) Investigation of membrane disruption in the reaction catalyzed by cholesterol oxidase. Biochemistry 36:6133–6140

    PubMed  CAS  Google Scholar 

  • Gimpl G, Klein U, Reilander H, Fahrenholz F (1995) Expression of the human oxytocin receptor in baculovirus-infected insect cells: high-affinity binding is induced by a cholesterol–cyclodextrin complex. Biochemistry 34:13794–13801

    PubMed  CAS  Google Scholar 

  • Gimpl G, Burger K, Fahrenholz F (1997) Cholesterol as modulator of receptor function. Biochemistry 36:10959–10974

    PubMed  CAS  Google Scholar 

  • Gronberg L, Slotte JP (1990) Cholesterol oxidase catalyzed oxidation of cholesterol in mixed lipid monolayers: effects of surface pressure and phospholipid composition on catalytic activity. Biochemistry 29:3173–3178

    PubMed  CAS  Google Scholar 

  • Hao M, Lin SX, Karylowski OJ, Wustner D, McGraw TE, Maxfield FR (2002) Vesicular and non-vesicular sterol transport in living cells. The endocytic recycling compartment is a major sterol storage organelle. J Biol Chem 277:609–617

    PubMed  CAS  Google Scholar 

  • Heczkova B, Slotte JP (2006) Effect of anti-tumor ether lipids on ordered domains in model membranes. FEBS Lett 580:2471–2476

    PubMed  CAS  Google Scholar 

  • Hyslop PA, Morel B, Sauerheber RD (1990) Organization and interaction of cholesterol and phosphatidylcholine in model bilayer membranes. Biochemistry 29:1025–1038

    PubMed  CAS  Google Scholar 

  • Irie T, Fukunaga K, Pitha J (1992) Hydroxypropylcyclodextrins in parenteral use. I: lipid dissolution and effects on lipid transfers in vitro. J Pharm Sci 81:521–523

    PubMed  CAS  Google Scholar 

  • Iwamoto M, Morita I, Fukuda M, Murota S, Ando S, Ohno-Iwashita Y (1997) A biotinylated perfringolysin O derivative: a new probe for detection of cell surface cholesterol. Biochim Biophys Acta 1327:222–230

    PubMed  CAS  Google Scholar 

  • Kan CC, Yan J, Bittman R (1992) Rates of spontaneous exchange of synthetic radiolabeled sterols between lipid vesicles. Biochemistry 31:1866–1874

    PubMed  CAS  Google Scholar 

  • Keilbaugh SA, Thornton ER (1983) Synthesis and photoreactivity of cholesteryl diazoacetate: a novel photolabeling reagent. J Am Chem Soc 105:3283–3286

    CAS  Google Scholar 

  • Kilsdonk EP, Yancey PG, Stoudt GW, Bangerter FW, Johnson WJ, Phillips MC, Rothblat GH (1995) Cellular cholesterol efflux mediated by cyclodextrins. J Biol Chem 270:17250–17256

    PubMed  CAS  Google Scholar 

  • Kinsky SC, Luse SA, Zopf D, van Deenen LL, Haxby J (1967) Interaction of filipin and derivatives with erythrocyte membranes and lipid dispersions: electron microscopic observations. Biochim Biophys Acta 135:844–861

    PubMed  CAS  Google Scholar 

  • Klein U, Gimpl G, Fahrenholz F (1995) Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34:13784–13793

    PubMed  CAS  Google Scholar 

  • Kramer W, Kurz G (1983) Photolabile derivatives of bile salts. Synthesis and suitability for photoaffinity labeling. J Lipid Res 24:910–923

    PubMed  CAS  Google Scholar 

  • Kramer W, Girbig F, Corsiero D, Burger K, Fahrenholz F, Jung C, Muller G (2003) Intestinal cholesterol absorption: identification of different binding proteins for cholesterol and cholesterol absorption inhibitors in the enterocyte brush border membrane. Biochim Biophys Acta 1633:13–26

    PubMed  CAS  Google Scholar 

  • Kramer-Albers EM, Gehrig-Burger K, Thiele C, Trotter J, Nave KA (2006) Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia. J Neurosci 26:11743–11752

    PubMed  Google Scholar 

  • Lada AT, Davis M, Kent C, Chapman J, Tomoda H, Omura S, Rudel LL (2004) Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell based fluorescence assay: individual ACAT uniqueness. J Lipid Res 45:378–386

    PubMed  CAS  Google Scholar 

  • Lafont F, Simons K, Ikonen E (1995) Dissecting the molecular mechanisms of polarized membrane traffic: reconstitution of three transport steps in epithelial cells using streptolysin-O permeabilization. Cold Spring Harb Symp Quant Biol 60:753–762

    PubMed  CAS  Google Scholar 

  • Lange Y (1991) Disposition of intracellular cholesterol in human fibroblasts. J Lipid Res 32:329–339

    PubMed  CAS  Google Scholar 

  • Lange Y (1992) Tracking cell cholesterol with cholesterol oxidase. J Lipid Res 33:315–321

    PubMed  CAS  Google Scholar 

  • Lange Y, Matthies HJ (1984) Transfer of cholesterol from its site of synthesis to the plasma membrane. J Biol Chem 259:14624–14630

    PubMed  CAS  Google Scholar 

  • Lange Y, Dolde J, Steck TL (1981) The rate of transmembrane movement of cholesterol in the human erythrocyte. J Biol Chem 256:5321–5323

    PubMed  CAS  Google Scholar 

  • Lange Y, Matthies H, Steck TL (1984) Cholesterol oxidase susceptibility of the red cell membrane. Biochim Biophys Acta 769:551–562

    PubMed  CAS  Google Scholar 

  • Lange Y, Swaisgood MH, Ramos BV, Steck TL (1989) Plasma membranes contain half the phospholipid and 90% of the cholesterol and sphingomyelin in cultured human fibroblasts. J Biol Chem 264:3786–3793

    PubMed  CAS  Google Scholar 

  • Lange Y, Echevarria F, Steck TL (1991) Movement of zymosterol, a precursor of cholesterol, among three membranes in human fibroblasts. J Biol Chem 266:21439–21443

    PubMed  CAS  Google Scholar 

  • Lange Y, Strebel F, Steck TL (1993) Role of the plasma membrane in cholesterol esterification in rat hepatoma cells. J Biol Chem 268:13838–13843

    PubMed  CAS  Google Scholar 

  • Lange Y, Ye J, Steck TL (2004) How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids. Proc Natl Acad Sci USA 101:11664–11667

    PubMed  CAS  Google Scholar 

  • Lange Y, Ye J, Steck TL (2005) Activation of membrane cholesterol by displacement from phospholipids. J Biol Chem 280:36126–36131

    PubMed  CAS  Google Scholar 

  • Li J, Vrielink A, Brick P, Blow DM (1993) Crystal structure of cholesterol oxidase complexed with a steroid substrate: implications for flavin adenine dinucleotide dependent alcohol oxidases. Biochemistry 32:11507–11515

    PubMed  CAS  Google Scholar 

  • Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P (2006) NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. J Biol Chem 281:36710–36723

    PubMed  CAS  Google Scholar 

  • Liscum L, Munn NJ (1999) Intracellular cholesterol transport. Biochim Biophys Acta 1438:19–37

    PubMed  CAS  Google Scholar 

  • Lopes SC, Goormaghtigh E, Cabral BJ, Castanho MA (2004) Filipin orientation revealed by linear dichroism. Implication for a model of action. J Am Chem Soc 126:5396–5402

    PubMed  CAS  Google Scholar 

  • Loura LM, Fedorov A, Prieto M (2001) Exclusion of a cholesterol analog from the cholesterol-rich phase in model membranes. Biochim Biophys Acta 1511:236–243

    PubMed  CAS  Google Scholar 

  • MacLachlan J, Wotherspoon AT, Ansell RO, Brooks CJ (2000) Cholesterol oxidase: sources, physical properties and analytical applications. J Steroid Biochem Mol Biol 72:169–195

    PubMed  CAS  Google Scholar 

  • Martin OC, Comly ME, Blanchette-Mackie EJ, Pentchev PG, Pagano RE (1993) Cholesterol deprivation affects the fluorescence properties of a ceramide analog at the Golgi apparatus of living cells. Proc Natl Acad Sci USA 90:2661–2665

    PubMed  CAS  Google Scholar 

  • Mattjus P, Bittman R, Vilcheze C, Slotte JP (1995) Lateral domain formation in cholesterol/phospholipid monolayers as affected by the sterol side chain conformation. Biochim Biophys Acta 1240:237–247

    PubMed  Google Scholar 

  • Matyash V, Geier C, Henske A, Mukherjee S, Hirsh D, Thiele C, Grant B, Maxfield FR, Kurzchalia TV (2001) Distribution and transport of cholesterol in Caenorhabditis elegans. Mol Biol Cell 12:1725–1736

    PubMed  CAS  Google Scholar 

  • McIntosh AL, Gallegos AM, Atshaves BP, Storey SM, Kannoju D, Schroeder F (2003) Fluorescence and multiphoton imaging resolve unique structural forms of sterol in membranes of living cells. J Biol Chem 278:6384–6403

    PubMed  CAS  Google Scholar 

  • McIntyre JC, Sleight RG (1991) Fluorescence assay for phospholipid membrane asymmetry. Biochemistry 30:11819–11827

    PubMed  CAS  Google Scholar 

  • Megha, Bakht O, London E (2006) Cholesterol precursors stabilize ordinary and ceramide-rich ordered lipid domains (lipid rafts) to different degrees. Implications for the Bloch hypothesis and sterol biosynthesis disorders. J Biol Chem 281:21903–21913

  • Middlemas DS, Raftery MA (1987) Identification of subunits of acetylcholine receptor that interact with a cholesterol photoaffinity probe. Biochemistry 26:1219–1223

    PubMed  CAS  Google Scholar 

  • Mintzer EA, Waarts BL, Wilschut J, Bittman R (2002) Behavior of a photoactivatable analog of cholesterol, 6- photocholesterol, in model membranes. FEBS Lett 510:181–184

    PubMed  CAS  Google Scholar 

  • Mobius W, Ohno-Iwashita Y, van Donselaar EG, Oorschot VM, Shimada Y, Fujimoto T, Heijnen HF, Geuze HJ, Slot JW (2002) Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J Histochem Cytochem 50:43–55

    PubMed  CAS  Google Scholar 

  • Morrot G, Bureau JF, Roux M, Maurin L, Favre E, Devaux PF (1987) Orientation and vertical fluctuations of spin-labeled analogues of cholesterol and androstanol in phospholipid bilayers. Biochim Biophys Acta 897:341–345

    PubMed  CAS  Google Scholar 

  • Mukherjee S, Chattopadhyay A (1996) Membrane organization at low cholesterol concentrations: a study using 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled cholesterol. Biochemistry 35:1311–1322

    PubMed  CAS  Google Scholar 

  • Mukherjee S, Zha X, Tabas I, Maxfield FR (1998) Cholesterol distribution in living cells: fluorescence imaging using dehydroergosterol as a fluorescent cholesterol analog. Biophys J 75:1915–1925

    PubMed  CAS  Google Scholar 

  • Muller P, Herrmann A (2002) Rapid transbilayer movement of spin-labeled steroids in human erythrocytes and in liposomes. Biophys J 82:1418–1428

    PubMed  CAS  Google Scholar 

  • Nemecz G, Schroeder F (1991) Selective binding of cholesterol by recombinant fatty acid binding proteins. J Biol Chem 266:17180–17186

    PubMed  CAS  Google Scholar 

  • Nemecz G, Fontaine RN, Schroeder F (1988) A fluorescence and radiolabel study of sterol exchange between membranes. Biochim Biophys Acta 943:511–521

    PubMed  CAS  Google Scholar 

  • Ohgami N, Ko DC, Thomas M, Scott MP, Chang CC, Chang TY (2004) Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc Natl Acad Sci USA 101:12473–12478

    PubMed  CAS  Google Scholar 

  • Ohno-Iwashita Y, Iwamoto M, Ando S, Iwashita S (1992) Effect of lipidic factors on membrane cholesterol topology-mode of binding of theta-toxin to cholesterol in liposomes. Biochim Biophys Acta 1109:81–90

    PubMed  CAS  Google Scholar 

  • Ohtani Y, Irie T, Uekama K, Fukunaga K, Pitha J (1989) Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes. Eur J Biochem 186:17–22

    PubMed  CAS  Google Scholar 

  • Okamoto Y, Ninomiya H, Miwa S, Masaki T (2000) Cholesterol oxidation switches the internalization pathway of endothelin receptor type A from caveolae to clathrin-coated pits in Chinese hamster ovary cells. J Biol Chem 275:6439–6446

    PubMed  CAS  Google Scholar 

  • Orci L, Perrelet A, Montesano R (1983) Differential filipin labeling of the luminal membranes lining the pancreatic acinus. J Histochem Cytochem 31:952–955

    PubMed  CAS  Google Scholar 

  • Palmer M (2001) The family of thiol-activated, cholesterol-binding cytolysins. Toxicon 39:1681–1689

    PubMed  CAS  Google Scholar 

  • Patzer EJ, Wagner RR (1978) Cholesterol oxidase as a probe for studying membrane organisation. Nature 274:394–395

    PubMed  CAS  Google Scholar 

  • Pelletier RM, Vitale ML (1994) Filipin vs enzymatic localization of cholesterol in guinea pig, mink, and mallard duck testicular cells. J Histochem Cytochem 42:1539–1554

    PubMed  CAS  Google Scholar 

  • Petrescu AD, Gallegos AM, Okamura Y, Strauss JF III, Schroeder F (2001) Steroidogenic acute regulatory protein binds cholesterol and modulates mitochondrial membrane sterol domain dynamics. J Biol Chem 276:36970–36982

    PubMed  CAS  Google Scholar 

  • Pipalia NH, Hao M, Mukherjee S, Maxfield FR (2007) Sterol, protein and lipid trafficking in Chinese hamster ovary cells with Niemann-Pick type C1 defect. Traffic 8:130–141

    PubMed  CAS  Google Scholar 

  • Prigent D, Alouf JE (1976) Interaction of steptolysin O with sterols. Biochim Biophys Acta 443:288–300

    PubMed  CAS  Google Scholar 

  • Pucadyil TJ, Chattopadhyay A (2006) Role of cholesterol in the function and organization of G-protein coupled receptors. Prog Lipid Res 45:295–333

    PubMed  CAS  Google Scholar 

  • Radhakrishnan A, McConnell HM (2000) Chemical activity of cholesterol in membranes. Biochemistry 39:8119–8124

    PubMed  CAS  Google Scholar 

  • Ramachandran R, Heuck AP, Tweten RK, Johnson AE (2002) Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Nat Struct Biol 9:823–827

    PubMed  CAS  Google Scholar 

  • Reid PC, Sakashita N, Sugii S, Ohno-Iwashita Y, Shimada Y, Hickey WF, Chang TY (2004) A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res 45:582–591

    PubMed  CAS  Google Scholar 

  • Robinson JM, Karnovsky MJ (1980) Evaluation of the polyene antibiotic filipin as a cytochemical probe for membrane cholesterol. J Histochem Cytochem 28:161–168

    PubMed  CAS  Google Scholar 

  • Rossjohn J, Feil SC, McKinstry WJ, Tweten RK, Parker MW (1997) Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form. Cell 89:685–692

    PubMed  CAS  Google Scholar 

  • Rukmini R, Rawat SS, Biswas SC, Chattopadhyay A (2001) Cholesterol organization in membranes at low concentrations: effects of curvature stress and membrane thickness. Biophys J 81:2122–2134

    PubMed  CAS  Google Scholar 

  • Scheidt HA, Muller P, Herrmann A, Huster D (2003) The potential of fluorescent and spin-labeled steroid analogs to mimic natural cholesterol. J Biol Chem 278:45563–45569

    PubMed  CAS  Google Scholar 

  • Schroeder F (1984) Fluorescent sterols: probe molecules of membrane structure and function. Prog Lipid Res 23:97–113

    PubMed  CAS  Google Scholar 

  • Schroeder F, Dempsey ME, Fischer RT (1985) Sterol and squalene carrier protein interactions with fluorescent delta 5,7,9(11)-cholestatrien-3 beta-ol. J Biol Chem 260:2904–2911

    PubMed  CAS  Google Scholar 

  • Schroeder F, Nemecz G, Gratton E, Barenholz Y, Thompson TE (1988) Fluorescence properties of cholestatrienol in phosphatidylcholine bilayer vesicles. Biophys Chem 32:57–72

    PubMed  CAS  Google Scholar 

  • Schroeder F, Butko P, Nemecz G, Scallen TJ (1990) Interaction of fluorescent delta 5,7,9(11),22-ergostatetraen-3 beta-ol with sterol carrier protein-2. J Biol Chem 265:151–157

    PubMed  CAS  Google Scholar 

  • Schroeder F, Nemecz G, Wood WG, Joiner C, Morrot G, Ayraut-Jarrier M, Devaux PF (1991) Transmembrane distribution of sterol in the human erythrocyte. Biochim Biophys Acta 1066:183–192

    PubMed  CAS  Google Scholar 

  • Schroeder F, Woodford JK, Kavecansky J, Wood WG, Joiner C (1995) Cholesterol domains in biological membranes. Mol Membr Biol 12:113–119

    PubMed  CAS  Google Scholar 

  • Schroeder F, Frolov AA, Murphy EJ, Atshaves BP, Jefferson JR, Pu L, Wood WG, Foxworth WB, Kier AB (1996) Recent advances in membrane cholesterol domain dynamics and intracellular cholesterol trafficking. Proc Soc Exp Biol Med 213:150–177

    PubMed  CAS  Google Scholar 

  • Severs NJ, Simons HL (1983) Failure of filipin to detect cholesterol-rich domains in smooth muscle plasma membrane. Nature 303:637–638

    PubMed  CAS  Google Scholar 

  • Shimada Y, Maruya M, Iwashita S, Ohno-Iwashita Y (2002) The C-terminal domain of perfringolysin O is an essential cholesterol-binding unit targeting to cholesterol-rich microdomains. Eur J Biochem 269:6195–6203

    PubMed  CAS  Google Scholar 

  • Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572

    PubMed  CAS  Google Scholar 

  • Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39

    PubMed  CAS  Google Scholar 

  • Simons M, Kramer EM, Thiele C, Stoffel W, Trotter J (2000) Assembly of myelin by association of proteolipid protein with cholesterol- and galactosylceramide-rich membrane domains. J Cell Biol 151:143–154

    PubMed  CAS  Google Scholar 

  • Slotte JP, Mattjus P (1995) Visualization of lateral phases in cholesterol and phosphatidylcholine monolayers at the air/water interface–a comparative study with two different reporter molecules. Biochim Biophys Acta 1254:22–29

    PubMed  Google Scholar 

  • Slotte JP, Hedstrom G, Rannstrom S, Ekman S (1989) Effects of sphingomyelin degradation on cell cholesterol oxidizability and steady-state distribution between the cell surface and the cell interior. Biochim Biophys Acta 985:90–96

    PubMed  CAS  Google Scholar 

  • Smart EJ, Ying YS, Conrad PA, Anderson RG (1994) Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J Cell Biol 127:1185–1197

    PubMed  CAS  Google Scholar 

  • Smutzer G, Crawford BF, Yeagle PL (1986) Physical properties of the fluorescent sterol probe dehydroergosterol. Biochim Biophys Acta 862:361–371

    PubMed  CAS  Google Scholar 

  • Sparrow CP, Patel S, Baffic J, Chao YS, Hernandez M, Lam MH, Montenegro J, Wright SD, Detmers PA (1999) A fluorescent cholesterol analog traces cholesterol absorption in hamsters and is esterified in vivo and in vitro. J Lipid Res 40:1747–1757

    PubMed  CAS  Google Scholar 

  • Spencer TA, Wang P, Li D, Russel JS, Blank DH, Huuskonen J, Fielding PE, Fielding CJ (2004) Benzophenone-containing cholesterol surrogates: synthesis and biological evaluation. J Lipid Res 45:1510–1518

    PubMed  CAS  Google Scholar 

  • Spencer TA, Wang P, Popovici-Muller JV, Peltan ID, Fielding PE, Fielding CJ (2006) Preparation and biochemical evaluation of fluorenone-containing lipid analogs. Bioorg Med Chem Lett 16:3000–3004

    PubMed  CAS  Google Scholar 

  • Steck TL, Ye J, Lange Y (2002) Probing red cell membrane cholesterol movement with cyclodextrin. Biophys J 83:2118–2125

    PubMed  CAS  Google Scholar 

  • Steer CJ, Bisher M, Blumenthal R, Steven AC (1984) Detection of membrane cholesterol by filipin in isolated rat liver coated vesicles is dependent upon removal of the clathrin coat. J Cell Biol 99:315–319

    PubMed  CAS  Google Scholar 

  • Stoffel W, Klotzbucher R (1978) Inhibition of cholesterol synthesis in cultured cells by 25-azidonorcholesterol. Hoppe Seylers Z Physiol Chem 359:199–209

    PubMed  CAS  Google Scholar 

  • Sugii S, Reid PC, Ohgami N, Shimada Y, Maue RA, Ninomiya H, Ohno-Iwashita Y, Chang TY (2003) Biotinylated theta toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-pick type C1 cells. J Lipid Res 44, 1033

    PubMed  CAS  Google Scholar 

  • Tampe R, von Lukas A, Galla HJ (1991) Glycophorin-induced cholesterol-phospholipid domains in dimyristoylphosphatidylcholine bilayer vesicles. Biochemistry 30:4909–4916

    PubMed  CAS  Google Scholar 

  • Tashiro Y, Yamazaki T, Shimada Y, Ohno-Iwashita Y, Okamoto K (2004) Axon-dominant localization of cell-surface cholesterol in cultured hippocampal neurons and its disappearance in Niemann-Pick type C model cells. Eur J Neurosci 20:2015–2021

    PubMed  Google Scholar 

  • Terasawa T, Ikekawa N, Morisaki M (1986) Syntheses of cholesterol analogs with a carbene-generating substituent on the side chain. Chem Pharm Bull 34:931–934

    CAS  Google Scholar 

  • Thiele C, Hannah MJ, Fahrenholz F, Huttner WB (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2:42–49

    PubMed  CAS  Google Scholar 

  • Tserentsoodol N, Sztein J, Campos M, Gordiyenko NV, Fariss RN, Lee JW, Fliesler SJ, Rodriguez IR (2006) Uptake of cholesterol by the retina occurs primarily via a low density lipoprotein receptor-mediated process. Mol Vis 12:1306–1318

    PubMed  CAS  Google Scholar 

  • Tweten RK, Parker MW, Johnson AE (2001) The cholesterol-dependent cytolysins. Curr Top Microbiol Immunol 257:15–33

    PubMed  CAS  Google Scholar 

  • Vainio S, Jansen M, Koivusalo M, Rog T, Karttunen M, Vattulainen I, Ikonen E (2006) Significance of sterol structural specificity. Desmosterol cannot replace cholesterol in lipid rafts. J Biol Chem 281:348–355

    PubMed  CAS  Google Scholar 

  • Vaughan AM, Oram JF (2005) ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J Biol Chem 280:30150–30157

    PubMed  CAS  Google Scholar 

  • Verkleij AJ, de Kruijff B, Gerritsen WF, Demel RA, van Deenen LL, Ververgaert PH (1973) Freeze-etch electron microscopy of erythrocytes, Acholeplasma laidlawii cells and liposomal membranes after the action of filipin and amphotericin B. Biochim Biophys Acta 291:577–581

    PubMed  CAS  Google Scholar 

  • Vrielink A, Lloyd LF, Blow DM (1991) Crystal structure of cholesterol oxidase from Brevibacterium sterolicum refined at 1.8 A resolution. J Mol Biol 219:533–554

    PubMed  CAS  Google Scholar 

  • Waheed AA, Shimada Y, Heijnen HF, Nakamura M, Inomata M, Hayashi M, Iwashita S, Slot JW, Ohno-Iwashita Y (2001) Selective binding of perfringolysin O derivative to cholesterol-rich membrane microdomains (rafts). Proc Natl Acad Sci USA 98:4926–4931

    PubMed  CAS  Google Scholar 

  • Wang MM, Olsher M, Sugar IP, Chong PL (2004) Cholesterol superlattice modulates the activity of cholesterol oxidase in lipid membranes. Biochemistry 43:2159–2166

    PubMed  CAS  Google Scholar 

  • Watson KC, Kerr EJ (1974) Sterol structural requirements for inhibition of streptolysin O activity. Biochem J 140:95–98

    PubMed  CAS  Google Scholar 

  • Wiegand V, Chang TY, Strauss JF III, Fahrenholz F, Gimpl G (2003) Transport of plasma membrane-derived cholesterol and the function of Niemann-Pick C1 Protein. FASEB J 17:782–784

    PubMed  CAS  Google Scholar 

  • Wustner D (2007) Plasma membrane sterol distribution resembles the surface topography of living cells. Mol Biol Cell 18:211–228

    PubMed  CAS  Google Scholar 

  • Wustner D, Herrmann A, Hao M, Maxfield FR (2002) Rapid nonvesicular transport of sterol between the plasma membrane domains of polarized hepatic cells. J Biol Chem 277:30325–30336

    PubMed  CAS  Google Scholar 

  • Wustner D, Mondal M, Huang A, Maxfield FR (2004) Different transport routes for high density lipoprotein and its associated free sterol in polarized hepatic cells. J Lipid Res 45:427–437

    PubMed  Google Scholar 

  • Wustner D, Mondal M, Tabas I, Maxfield FR (2005) Direct observation of rapid internalization and intracellular transport of sterol by macrophage foam cells. Traffic 6:396–412

    PubMed  Google Scholar 

  • Xu X, London E (2000) The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation. Biochemistry 39:843–849

    PubMed  CAS  Google Scholar 

  • Yancey PG, Rodrigueza WV, Kilsdonk EP, Stoudt GW, Johnson WJ, Phillips MC, Rothblat GH (1996) Cellular cholesterol efflux mediated by cyclodextrins. Demonstration of kinetic pools and mechanism of efflux. J Biol Chem 271:16026–16034

    PubMed  CAS  Google Scholar 

  • Yeagle PL (1985) Cholesterol and the cell membrane. Biochim Biophys Acta 822:267–287

    PubMed  CAS  Google Scholar 

  • Yeagle PL, Albert AD, Boesze-Battaglia K, Young J, Frye J (1990) Cholesterol dynamics in membranes. Biophys J 57:413–424

    Article  PubMed  CAS  Google Scholar 

  • Yin Y, Liu P, Anderson RG, Sampson NS (2002) Construction of a catalytically inactive cholesterol oxidase mutant: investigation of the interplay between active site-residues glutamate 361 and histidine 447. Arch Biochem Biophys 402:235–242

    PubMed  CAS  Google Scholar 

  • Yue QK, Kass IJ, Sampson NS, Vrielink A (1999) Crystal structure determination of cholesterol oxidase from Streptomyces and structural characterization of key active site mutants. Biochemistry 38:4277–4286

    PubMed  CAS  Google Scholar 

  • Zhang W, McIntosh AL, Xu H, Wu D, Gruninger T, Atshaves B, Liu JC, Schroeder F (2005) Structural analysis of sterol distributions in the plasma membrane of living cells. Biochemistry 44:2864–2884

    PubMed  CAS  Google Scholar 

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  1. Institut für Biochemie, Johannes Gutenberg-University of Mainz, Becherweg 30, 55099, Mainz, Germany

    Gerald Gimpl & Katja Gehrig-Burger

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Correspondence to Gerald Gimpl.

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Gimpl, G., Gehrig-Burger, K. Cholesterol Reporter Molecules. Biosci Rep 27, 335–358 (2007). https://doi.org/10.1007/s10540-007-9060-1

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