Lipids function as essential structural components of membranes, as signalling molecules, as chemical identifiers of specific membranes and as energy storage molecules. The synthesis of lipids is non-uniformly distributed among a few cellular membranes, which requires most organelles to depend on lipid transport processes to achieve their full complement of lipids.
Organelles differ both quantitatively and qualitatively in their lipid content. In many organelles, the lipid composition of separate leaflets of the membrane bilayer is significantly different, which produces asymmetry across the bilayer — a situation that is maintained by ATP-dependent flippases.
Lipid transport between and within organelles is poorly understood, but a growing number of genes that are involved in these processes have been unambiguously identified, and their mechanisms of action are under active investigation. There is clear evidence that several lipids are transported between organelles by non-vesicular mechanisms that involve zones of apposition between donor and acceptor compartments, and macromolecular assemblies that involve multiple lipids and proteins.
Several dozen lipids participate in intra- and intercellular signalling processes. In most instances, the levels of signalling molecules are exceedingly low compared with the complement of structural lipids that is present in membranes.
Lipids adopt defined phases depending on their molecular structure and the physical conditions. In lipid mixtures, two fluid phases can coexist with different physical properties: liquid-disordered and liquid-ordered.
Liquid-ordered assemblies in biomembranes, known as lipid rafts, are small and transient but can coalesce and become stabilized during signalling and vesicle budding. How proteins contribute to phase separation and preferentially distribute into one of the two different phases (or at their interface) is presently unclear.
Throughout the biological world, a 30 Å hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?
Your institute does not have access to this article
Open Access articles citing this article.
Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance
Oncogenesis Open Access 09 August 2022
Particle and Fibre Toxicology Open Access 06 August 2022
Nature Communications Open Access 24 June 2022
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sud, M. et al. LMSD: LIPID MAPS structure database. Nucleic Acids Res. 35, D527–D532 (2007).
Feigenson, G. W. Phase behavior of lipid mixtures. Nature Chem. Biol. 2, 560–563 (2006).
Feigenson, G. W. Phase boundaries and biological membranes. Annu. Rev. Biophys. Biomol. Struct. 36, 63–77 (2007).
Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006). Cell biology studies, live-cell imaging and systems biology show that many of the multiple and subtly different pathways that animal viruses use to enter host cells require specific lipids.
van Meer, G. Cellular lipidomics. EMBO J. 24, 3159–3165 (2005).
Marsh, D. Lateral pressure profile, spontaneous curvature frustration, and the incorporation and conformation of proteins in membranes. Biophys. J. 93, 3884–3899 (2007).
Dowhan, W. & Bogdanov, M. in Biochemistry of Lipids, Lipoproteins and Membranes Vol. 36 (eds Vance, D. E. & Vance, J. E.) 1–35 (Elsevier, Amsterdam, 2002).
van Meer, G. & Lisman, Q. Sphingolipid transport: rafts and translocators. J. Biol. Chem. 277, 25855–25858 (2002).
Huang, J. & Feigenson, G. W. A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers. Biophys. J. 76, 2142–2157 (1999). The interactions of cholesterol with membrane lipid lead to abrupt jumps in cholesterol chemical potential because of the hydrophobic interaction, which forces phospholipid headgroups to shield cholesterol from water, as described here by the umbrella model.
Ali, M. R., Cheng, K. H. & Huang, J. Ceramide drives cholesterol out of the ordered lipid bilayer phase into the crystal phase in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/cholesterol/ceramide ternary mixtures. Biochemistry 45, 12629–12638 (2006).
Meyer zu Heringdorf, D. & Jakobs, K. H. Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim. Biophys. Acta 1768, 923–940 (2007).
Fernandis, A. Z. & Wenk, M. R. Membrane lipids as signaling molecules. Curr. Opin. Lipidol. 18, 121–128 (2007).
Kolesnick, R. & Hannun, Y. A. Ceramide and apoptosis. Trends Biochem. Sci. 24, 224–225 (1999).
Tepper, A. D. et al. Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology. J. Cell Biol. 150, 155–164 (2000).
Megha, Sawatzki, P., Kolter, T., Bittman, R. & London, E. Effect of ceramide N-acyl chain and polar headgroup structure on the properties of ordered lipid domains (lipid rafts). Biochim. Biophys. Acta 1768, 2205–2212 (2007).
Bell, R. M., Ballas, L. M. & Coleman, R. A. Lipid topogenesis. J. Lipid Res. 22, 391–403 (1981).
Sprong, H. et al. UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. J. Biol. Chem. 273, 25880–25888 (1998).
Rusinol, A. E., Cui, Z., Chen, M. H. & Vance, J. E. A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J. Biol. Chem. 269, 27494–27502 (1994). Provides evidence for stable physical associations between the ER and mitochondria, and also identifies biochemical properties of this compartment that are distinct from the individual organelles.
Pichler, H. et al. A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids. Eur. J. Biochem. 268, 2351–2361 (2001).
Futerman, A. H. & Riezman, H. The ins and outs of sphingolipid synthesis. Trends Cell Biol. 15, 312–318 (2005).
Henneberry, A. L., Wright, M. M. & McMaster, C. R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity. Mol. Biol. Cell 13, 3148–3161 (2002).
Voelker, D. R. Bridging gaps in phospholipid transport. Trends Biochem. Sci. 30, 396–404 (2005). Summarizes biochemical and genetic elements of non-vesicular phospholipid transport with highlighted emphasis on PtdSer transport processes in yeast.
Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).
Geta Tafesse, F. et al. Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J. Biol. Chem. 282, 17537–17547 (2007).
Li, Z. et al. Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochim. Biophys. Acta 1771, 1186–1194 (2007).
Kobayashi, T. et al. Separation and characterization of late endosomal membrane domains. J. Biol. Chem. 277, 32157–32164 (2002).
Matsuo, H. et al. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 303, 531–534 (2004).
Kolter, T. & Sandhoff, K. Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol. 21, 81–103 (2005).
Vance, D. E. & Vance, J. E. Biochemistry of Lipids, Lipoproteins and Membranes (Elsevier, Amsterdam, 2002).
Nagle, C. A. et al. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. J. Biol. Chem. 282, 14807–14815 (2007).
Choi, J. Y., Wu, W. I. & Voelker, D. R. Phosphatidylserine decarboxylases as genetic and biochemical tools for studying phospholipid traffic. Anal. Biochem. 347, 165–175 (2005).
Daum, G. Lipids of mitochondria. Biochim. Biophys. Acta 822, 1–42 (1985).
Strauss, J. F., Kishida, T., Christenson, L. K., Fujimoto, T. & Hiroi, H. START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Mol. Cell. Endocrinol. 202, 59–65 (2003).
Devaux, P. F. & Morris, R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic 5, 241–246 (2004).
Daleke, D. L. Phospholipid flippases. J. Biol. Chem. 282, 821–825 (2007).
Pomorski, T. & Menon, A. K. Lipid flippases and their biological functions. Cell. Mol. Life Sci. 63, 2908–2921 (2006).
Anglin, T. C., Liu, J. & Conboy, J. C. Facile lipid flip-flop in a phospholipid bilayer induced by gramicidin A measured by sum-frequency vibrational spectroscopy. Biophys. J. 92, L01–L03 (2007).
Papadopulos, A. et al. Flippase activity detected with unlabeled lipids by shape changes of giant unilamellar vesicles. J. Biol. Chem. 282, 15559–15568 (2007).
López-Montero, I. et al. Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J. Biol. Chem. 280, 25811–25819 (2005).
Ganong, B. R. & Bell, R. M. Transmembrane movement of phosphatidylglycerol and diacylglycerol sulfhydryl analogues. Biochemistry 23, 4977–4983 (1984).
Bai, J. & Pagano, R. E. Measurement of spontaneous transfer and transbilayer movement of BODIPY-labeled lipids in lipid vesicles. Biochemistry 36, 8840–8848 (1997).
Steck, T. L., Ye, J. & Lange, Y. Probing red cell membrane cholesterol movement with cyclodextrin. Biophys. J. 83, 2118–2125 (2002).
Cullis, P. R. et al. Influence of pH gradients on the transbilayer transport of drugs, lipids, peptides and metal ions into large unilamellar vesicles. Biochim. Biophys. Acta 1331, 187–211 (1997).
Kol, M. A., de Kroon, A. I., Killian, J. A. & de Kruijff, B. Transbilayer movement of phospholipids in biogenic membranes. Biochemistry 43, 2673–2681 (2004). Summarizes the data and hypotheses that support a generic system for the non-selective transbilayer movement of lipids in the ER of eukaryotes and in the cytoplasmic membranes of bacteria.
Helenius, J. et al. Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein. Nature 415, 447–450 (2002).
Alaimo, C. et al. Two distinct but interchangeable mechanisms for flipping of lipid-linked oligosaccharides. EMBO J. 25, 967–976 (2006).
Graham, T. R. Flippases and vesicle-mediated protein transport. Trends Cell Biol. 14, 670–677 (2004). Summarizes important relationships between vesicular protein traffic and transbilayer phospholipid transport by P-type ATPases.
Pomorski, T. et al. Drs2p-related P-type ATPases Dnf1p and Dnf2p are required for phospholipid translocation across the yeast plasma membrane and serve a role in endocytosis. Mol. Biol. Cell 14, 1240–1254 (2003). An important paper defining the participation of plasma membrane P-type ATPases in yeast in the transbilayer movement of aminoglycerophospholipids and their interplay with endocytic processes.
Riekhof, W. R. & Voelker, D. R. Uptake and utilization of lyso-phosphatidylethanolamine by Saccharomyces cerevisiae. J. Biol. Chem. 281, 36588–36596 (2006).
Riekhof, W. R. et al. Lyso-phosphatidylcholine metabolism in Saccharomyces cerevisiae. The role of P-type ATPases in transport and a broad specificity acyltransferase in acylation. J. Biol. Chem. 21 Oct 2007 (doi:10.1074/jbc.M706718200)
Natarajan, P., Wang, J., Hua, Z. & Graham, T. R. Drs2p-coupled aminophospholipid translocase activity in yeast Golgi membranes and relationship to in vivo function. Proc. Natl. Acad. Sci. USA 101, 10614–10619 (2004).
Alder-Baerens, N., Lisman, Q., Luong, L., Pomorski, T. & Holthuis, J. C. Loss of P4 ATPases Drs2p and Dnf3p disrupts aminophospholipid transport and asymmetry in yeast post-Golgi secretory vesicles. Mol. Biol. Cell 17, 1632–1642 (2006).
Wang, X. et al. C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1. Nature Cell Biol. 9, 541–549 (2007).
Züllig, S. et al. Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apoptosis. Curr. Biol. 17, 994–999 (2007).
van Meer, G. & Simons, K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J. 5, 1455–1464 (1986).
Young, W. W. Jr, Lutz, M. S. & Blackburn, W. A. Endogenous glycosphingolipids move to the cell surface at a rate consistent with bulk flow estimates. J. Biol. Chem. 267, 12011–12015 (1992).
Baumann, N. A. et al. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration. Biochemistry 44, 5816–5826 (2005).
Simons, K. & van Meer, G. Lipid sorting in epithelial cells. Biochemistry 27, 6197–6202 (1988).
Halter, D. et al. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis J. Cell Biol. 179, 101–115 (2007). Suggests that the late Golgi protein FAPP2 transports GlcCer that is destined for complex glycolipid synthesis back to the ER, whereas GlcCer translocation to the cell surface depends on a proton gradient.
Smith, D. C. et al. The association of Shiga-like toxin with detergent-resistant membranes is modulated by glucosylceramide and is an essential requirement in the endoplasmic reticulum for a cytotoxic effect. Mol. Biol. Cell 17, 1375–1387 (2006).
Sharma, D. K. et al. Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J. Biol. Chem. 278, 7564–7572 (2003). Demonstrates the non-uniform distribution of fluorescent phospholipids within individual endosomes.
Wang, T. Y. & Silvius, J. R. Different sphingolipids show differential partitioning into sphingolipid/cholesterol-rich domains in lipid bilayers. Biophys. J. 79, 1478–1489 (2000).
Singh, R. D. et al. Inhibition of caveolar uptake, SV40 infection, and β1-integrin signaling by a nonnatural glycosphingolipid stereoisomer. J. Cell Biol. 176, 895–901 (2007).
Sleight, R. G. & Pagano, R. E. Rapid appearance of newly synthesized phosphatidylethanolamine at the plasma membrane. J. Biol. Chem. 258, 9050–9058 (1983).
Kaplan, M. R. & Simoni, R. D. Intracellular transport of phosphatidylcholine to the plasma membrane. J. Cell Biol. 101, 441–445 (1985).
Voelker, D. R. Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells. J. Biol. Chem. 265, 14340–14346 (1990).
Vance, J. E., Aasman, E. J. & Szarka, R. Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites of synthesis to the cell surface. J. Biol. Chem. 266, 8241–8247 (1991).
Wu, W. I. & Voelker, D. R. Characterization of phosphatidylserine transport to the locus of phosphatidylserine decarboxylase 2 in permeabilized yeast. J. Biol. Chem. 276, 7114–7121 (2001).
Schumacher, M. M., Choi, J. Y. & Voelker, D. R. Phosphatidylserine transport to the mitochondria is regulated by ubiquitination. J. Biol. Chem. 277, 51033–51042 (2002).
Papadopoulos, V. et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol. Sci. 27, 402–409 (2006). Summarizes the major protein constituents involved in non-vesicular import of cholesterol into the mitochondria of cells involved in steroid hormone synthesis.
Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003). An important paper defining the genetic and biochemical mechanisms for non-vesicular transport of ceramide between the ER and the Golgi apparatus.
Warnock, D. E., Lutz, M. S., Blackburn, W. A., Young, W. W. Jr & Baenziger, J. U. Transport of newly synthesized glucosylceramide to the plasma membrane by a non-Golgi pathway. Proc. Natl. Acad. Sci. USA 91, 2708–2712 (1994).
Trotter, P. J., Wu, W. I., Pedretti, J., Yates, R. & Voelker, D. R. A genetic screen for aminophospholipid transport mutants identifies the phosphatidylinositol 4-kinase, STT4p, as an essential component in phosphatidylserine metabolism. J. Biol. Chem. 273, 13189–13196 (1998).
Wu, W. I. & Voelker, D. R. Reconstitution of phosphatidylserine transport from chemically defined donor membranes to phosphatidylserine decarboxylase 2 implicates specific lipid domains in the process. J. Biol. Chem. 279, 6635–6642 (2004).
Raychaudhuri, S., Im, Y. J., Hurley, J. H. & Prinz, W. A. Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides. J. Cell Biol. 173, 107–119 (2006).
D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007). Shows that FAPP2, a protein that is associated with the generation of transport carriers from the Golgi to the plasma membrane, appears to be a GlcCer transfer protein with a pivotal role in complex GSL synthesis.
Awai, K., Xu, C., Tamot, B. & Benning, C. A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking. Proc. Natl Acad. Sci. USA 103, 10817–10822 (2006). Defines transport and intermembrane recognition components for moving phospholipids between the outer and inner chloroplast membranes.
Tefsen, B., Geurtsen, J., Beckers, F., Tommassen, J. & de Cock, H. Lipopolysaccharide transport to the bacterial outer membrane in spheroplasts. J. Biol. Chem. 280, 4504–4509 (2005).
Mousley, C. J., Tyeryar, K. R., Vincent-Pope, P. & Bankaitis, V. A. The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking. Biochim. Biophys. Acta 1771, 727–736 (2007).
Litvak, V., Dahan, N., Ramachandran, S., Sabanay, H. & Lev, S. Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nature Cell Biol. 7, 225–234 (2005).
Chernomordik, L., Kozlov, M. M. & Zimmerberg, J. Lipids in biological membrane fusion. J. Membr. Biol. 146, 1–14 (1995).
Shemesh, T., Luini, A., Malhotra, V., Burger, K. N. & Kozlov, M. M. Prefission constriction of Golgi tubular carriers driven by local lipid metabolism: a theoretical model. Biophys. J. 85, 3813–3827 (2003).
Gennis, R. B. Biomembranes. Molecular Structure and Function (Springer Verlag, New York, 1989).
Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). A careful reconstruction of synaptic vesicles shows that cholesterol and phospholipids (molar ratio 0.8) cover ∼70% of the surface while transmembrane helices cover 20%, with a lipid/protein ratio of 0.75 (w/w).
Dietrich, C., Volovyk, Z. N., Levi, M., Thompson, N. L. & Jacobson, K. Partitioning of Thy-1, GM1, and cross-linked phospholipid analogs into lipid rafts reconstituted in supported model membrane monolayers. Proc. Natl Acad. Sci. USA 98, 10642–10647 (2001).
Morse, S. A. Basalts and Phase Diagrams (Springer-Verlag, New York, 1980).
Parton, R. G. Ultrastructural localization of gangliosides: GM1 is concentrated in caveolae. J. Histochem. Cytochem. 42, 155–166 (1994).
Kusumi, A. et al. Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu. Rev. Biophys. Biomol. Struct. 34, 351–378 (2005). Biological membrane lipids and proteins are divided into regions, some tens of nanometres in size, which have distinct molecular components and properties.
Lagerholm, B. C., Weinreb, G. E., Jacobson, K. & Thompson, N. L. Detecting microdomains in intact cell membranes. Annu. Rev. Phys. Chem. 56, 309–336 (2005).
Feigenson, G. W. & Buboltz, J. T. Ternary phase diagram of dipalmitoyl-PC/dilauroyl-PC/cholesterol: nanoscopic domain formation driven by cholesterol. Biophys. J. 80, 2775–2788 (2001).
Meder, D., Moreno, M. J., Verkade, P., Vaz, W. L. & Simons, K. Phase coexistence and connectivity in the apical membrane of polarized epithelial cells. Proc. Natl Acad. Sci. USA 103, 329–334 (2006).
Kusumi, A., Koyama-Honda, I. & Suzuki, K. Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts. Traffic 5, 213–230 (2004).
Bollinger, C. R., Teichgraber, V. & Gulbins, E. Ceramide-enriched membrane domains. Biochim. Biophys. Acta 1746, 284–294 (2005).
Roux, A. et al. Role of curvature and phase transition in lipid sorting and fission of membrane tubules. EMBO J. 24, 1537–1545 (2005).
Chiantia, S., Kahya, N., Ries, J. & Schwille, P. Effects of ceramide on liquid-ordered domains investigated by simultaneous AFM and FCS. Biophys. J. 90, 4500–4508 (2006).
Sot, J., Bagatolli, L. A., Goni, F. M. & Alonso, A. Detergent-resistant, ceramide-enriched domains in sphingomyelin/ceramide bilayers. Biophys. J. 90, 903–914 (2006).
Anishkin, A., Sukharev, S. & Colombini, M. Searching for the molecular arrangement of transmembrane ceramide channels. Biophys. J. 90, 2414–2426 (2006).
Dietrich, C., Yang, B., Fujiwara, T., Kusumi, A. & Jacobson, K. Relationship of lipid rafts to transient confinement zones detected by single particle tracking. Biophys. J. 82, 274–284 (2002).
Sengupta, P., Baird, B. & Holowka, D. Lipid rafts, fluid/fluid phase separation, and their relevance to plasma membrane structure and function. Semin. Cell Dev. Biol. 18, 583–590 (2007).
Dibble, A. R. & Feigenson, G. W. Detection of coexisting fluid phospholipid phases by equilibrium Ca2+ binding: peptide-poor Lα and peptide-rich HII phase coexistence in gramicidin A′/phospholipid dispersions. Biochemistry 33, 12945–12953 (1994).
Lewis, R. N. et al. Studies of the minimum hydrophobicity of α-helical peptides required to maintain a stable transmembrane association with phospholipid bilayer membranes. Biochemistry 46, 1042–1054 (2007).
Jacobson, K., Mouritsen, O. G. & Anderson, R. G. Lipid rafts: at a crossroad between cell biology and physics. Nature Cell Biol. 9, 7–14 (2007). Proposes a model whereby transmembrane helices cover 15% of the surface and physically contact 30% of the membrane lipids, termed shell lipids. On receiving a signal, proteins control phase behaviour by combining their shell with similar lipid shells of other proteins.
Shogomori, H. et al. Palmitoylation and intracellular domain interactions both contribute to raft targeting of linker for activation of T cells. J. Biol. Chem. 280, 18931–18942 (2005).
Brown, D. A. Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology 21, 430–439 (2006). The use of detergent resistance to study the properties of biological membranes gives indirect information about protein and lipid phase preferences, but does not capture a snapshot of actual phase behaviour.
Epand, R. M. Cholesterol and the interaction of proteins with membrane domains. Prog. Lipid Res. 45, 279–294 (2006).
Hancock, J. F. Lipid rafts: contentious only from simplistic standpoints. Nature Rev. Mol. Cell Biol. 7, 456–462 (2006). A critical discussion of lipid rafts, stressing that protein–protein interactions make major contributions to the stability of lipid-based domains, and that proteins and specific lipids such as cholesterol may accumulate at and affect domain boundaries.
London, E. & Feigenson, G. W. Fluorescence quenching in model membranes. 2. Determination of local lipid environment of the calcium adenosinetriphosphatase from sarcoplasmic reticulum. Biochemistry 20, 1939–1948 (1981).
Caffrey, M. & Feigenson, G. W. Fluorescence quenching in model membranes. 3. Relationship between calcium adenosinetriphosphatase enzyme activity and the affinity of the protein for phosphatidylcholines with different acyl chain characteristics. Biochemistry 20, 1949–1961 (1981).
Esmann, M. & Marsh, D. Lipid–protein interactions with the Na, K-ATPase. Chem. Phys. Lipids 141, 94–104 (2006).
Soubias, O., Teague, W. E. & Gawrisch, K. Evidence for specificity in lipid–rhodopsin interactions. J. Biol. Chem. 281, 33233–33241 (2006).
Andersen, O. S. & Koeppe, R. E. 2nd. Bilayer thickness and membrane protein function: an energetic perspective. Annu. Rev. Biophys. Biomol. Struct. 36, 107–130 (2007).
Sharma, P. et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589 (2004).
Recktenwald, D. J. & McConnell, H. M. Phase equilibria in binary mixtures of phosphatidylcholine and cholesterol. Biochemistry 20, 4505–4510 (1981).
Wang, T. Y. & Silvius, J. R. Cholesterol does not induce segregation of liquid-ordered domains in bilayers modeling the inner leaflet of the plasma membrane. Biophys. J. 81, 2762–2773 (2001).
Kiessling, V., Crane, J. M. & Tamm, L. K. Transbilayer effects of raft-like lipid domains in asymmetric planar bilayers measured by single molecule tracking. Biophys. J. 91, 3313–3326 (2006).
van Meer, G., Halter, D., Sprong, H., Somerharju, P. & Egmond, M. R. ABC lipid transporters: extruders, flippases, or flopless activators? FEBS Lett. 580, 1171–1177 (2006).
Veatch, S. L. & Keller, S. L. Separation of liquid phases in giant vesicles of ternary mixtures of phospholipids and cholesterol. Biophys. J. 85, 3074–3083 (2003).
Veatch, S. L., Polozov, I. V., Gawrisch, K. & Keller, S. L. Liquid domains in vesicles investigated by NMR and fluorescence microscopy. Biophys. J. 86, 2910–2922 (2004).
Wassall, S. R. et al. Order from disorder, corralling cholesterol with chaotic lipids. The role of polyunsaturated lipids in membrane raft formation. Chem. Phys. Lipids 132, 79–88 (2004).
Veatch, S. L., Gawrisch, K. & Keller, S. L. Closed-loop miscibility gap and quantitative tie-lines in ternary membranes containing diphytanoyl PC. Biophys. J. 90, 4428–4436 (2006).
Bakht, O., Pathak, P. & London, E. Effect of the structure of lipids favoring disordered domain formation on the stability of cholesterol-containing ordered domains (lipid rafts): identification of multiple raft-stabilization mechanisms. Biophys. J. 93, 4307–4318 (2007). Polyunsaturated acyl chains of membrane lipids can effectively drive the formation of membrane rafts because of especially poor packing with cholesterol.
Kucerka, N., Tristram-Nagle, S. & Nagle, J. F. Closer look at structure of fully hydrated fluid phase DPPC bilayers. Biophys. J. 90, L83–L85 (2006).
Liu, K., Hua, Z., Nepute, J. A. & Graham, T. R. Yeast P4-ATPases Drs2p and Dnf1p are essential cargos of the NPFXD/Sla1p endocytic pathway. Mol. Biol. Cell 18, 487–500 (2007).
A family of storage lipids consisting of glycerol esterified to three fatty acids, forming the hydrophobic core of lipid droplets and blood lipoproteins together with steryl esters.
- Steryl ester
A family of storage lipids consisting of sterol esterified to one fatty acid, forming the hydrophobic core of lipid droplets and blood lipoproteins together with triacylglycerol molecules.
The characteristic of being polar on one side of the molecule and apolar on the opposite side.
- Lysosomal hydrolase
An enzyme that hydrolyses biomolecules in lysosomes.
A family of long-chain, unsaturated and methylated hydrocarbons that consist of varying numbers of isoprene units that terminate in an α-saturated isoprenoid group and contain an alcohol functional group. Dolicholphosphate and dolicholpyrophosphate anchor sugar molecules to the ER membrane for transfer to proteins in the ER lumen.
- Multivesicular body
An endosome containing internal vesicles that originate from inward budding. This direction of budding is away from the cytosol (opposite to the regular budding of transport vesicles) and a different molecular machinery has been found to be responsible.
- P-type ATPase
One of a family of membrane-embedded transporters that share a phosphorylated intermediate as part of their reaction cycle. It includes the Ca2+- and Na+/K+-ATPases and the P4 family of lipid flippases.
A mechanism (involving incompletely characterized components) that allows transmembrane movement of lipids and relaxation of lipid asymmetry on cell stimulation.
The coat protein of caveolae. It is anchored by a hydrophobic loop and 1–3 palmitoylated cysteines. Caveolin interacts with cholesterol and oligomerizes.
About this article
Cite this article
van Meer, G., Voelker, D. & Feigenson, G. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9, 112–124 (2008). https://doi.org/10.1038/nrm2330
Association between dietary fat quality indices with anthropometric measurements in children and adolescents
BMC Pediatrics (2022)
Particle and Fibre Toxicology (2022)
Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression
Journal of Experimental & Clinical Cancer Research (2022)
Nature Communications (2022)
Nature Communications (2022)