Review Article | Published:

Multidrug permeases and subcellular cholesterol transport

Nature Reviews Molecular Cell Biology volume 2, pages 657668 (2001) | Download Citation

Subjects

Abstract

Studies of Niemann–Pick C (NPC) and Tangier diseases have led to the identification of the causative genes, NPC1 and ABCA1, respectively. Characterization of their protein products shows that NPC1 and ABCA1 are permeases that belong to two different superfamilies of efflux pumps, which might be important in subcellular lipid and cholesterol transport.

Key points

  • The intercellular distribution and transport of cholesterol is a well-characterized process. However, the specific events that characterize the intracellular movement and distribution of cholesterol and other lipids are only poorly understood.

  • Low-density lipoprotein (LDL) particles carry cholesterol and other lipids from the liver to peripheral tissues, whereas high-density lipoprotein (HDL) particles facilitate the transport of these lipids from peripheral tissues back to the liver.

  • LDL particles are endocytosed and broken down in the endosomal–lysosomal system. Free cholesterol and presumably other lipid components of these particles exit the endosomal system and are transported to the plasma membrane.

  • From the plasma membrane, cholesterol can be transported to the endoplasmic reticulum and other intracellular sites. In addition, a plasma membrane ABC-type transporter facilitates the efflux of cholesterol and phospholipids onto HDL particles.

  • More than 10 ABC-type transporters are now known to facilitate the movement of cholesterol and other lipids across membrane bilayers. Their defective activities are associated with several diseases, exemplified by defects in the ABCA1 transporter that was recently shown to cause Tangier disease.

  • A member of a second family of transporters (RND), which depend on a proton motive force gradient for their function, was recently shown to reside in late endosomes where it facilitates lipid exit from this compartment. The defective action of this protein, NPC1, causes NPC1 disease, an autosomal-recessive lipidosis.

  • Recently, two other proteins, MLN64 and NPC2 were shown to reside in the endosomal–lysosomal system and might be involved in cholesterol and other lipid efflux from this system.

  • Increasing our understanding of the function of ABC and RND transporters in mammalian cells and their involvement in lipid transport and homeostasis should reveal the mechanisms of subcellular lipid movement and homeostasis, and should add to our understanding of disease pathogenesis when these transporters malfunction.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & A receptor mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).

  2. 2.

    & The role of intracellular cholesterol transport in cholesterol homeostasis. Trends Cell Biol. 6, 205–208 (1996).

  3. 3.

    & Intracellular cholesterol transport and compartmentation. J. Biol. Chem. 270, 15443–15446 (1995).

  4. 4.

    , & The biology of HMG-CoA reductase: the pros of contra-regulation. Trends Biochem. Sci. 21, 140–145 (1996).

  5. 5.

    , , , & Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J. Cell Biol. 117, 959–973 (1992).

  6. 6.

    , , , & Membrane-bound domain of HMG-CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41, 249–258 (1985).

  7. 7.

    , , & Molecular cloning and functional expression of human acyl-coenzyme A: cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J. Biol. Chem. 268, 20747–20755 (1993).

  8. 8.

    & in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 2705–2716 (McGraw–Hill, New York, 2001).

  9. 9.

    , & Distribution of glycosphingolipids in the serum lipoproteins of normal human subjects and patients with hypo- and hyperlipidemias. J. Lipid Res. 17, 125–131 (1976).

  10. 10.

    Compartmentation of cholesterol within the cell. Curr. Opin. Lipidol. 5, 221–226 (1994).

  11. 11.

    et al. Recent advances in membrane cholesterol domain dynamics and intracellular cholesterol trafficking. Proc. Soc. Exp. Biol. Med. 213, 150–177 (1996).

  12. 12.

    & Intracellular transport of cholesterol to the plasma membrane. J. Biol. Chem. 257, 14256–14262 (1982).

  13. 13.

    & Cholesterol and vesicular stomatitis virus G protein take separate routes from the endoplasmic reticulum to the plasma membrane. J. Biol. Chem. 265, 1919–1923 (1990).

  14. 14.

    & Transport of cholesterol from the endoplasmic reticulum to the plasma membrane. J. Cell Biol. 101, 446–453 (1985).

  15. 15.

    et al. Intracellular trafficking of cholesterol monitored with a cyclodextrin. J. Biol. Chem. 271, 21604–21613 (1996).

  16. 16.

    , , , & Translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the endoplasmic reticulum for esterification may require common cellular factors involved in cholesterol egress from the acidic compartments (lysosomes/endosomes). Biochim. Biophys. Acta 1254, 283–294 (1995).

  17. 17.

    , , & Role of Niemann–Pick type C1 protein in intracellular trafficking of low density lipoprotein-derived cholesterol. J. Biol. Chem. 275, 4013–4021 (2000).This work describes for the first time that LDL-derived cholesterol is rapidly transported to the plasma membrane, independently of the function of the NPC1 protein, which was previously thought to regulate such transport.

  18. 18.

    , , & Cholesterol movement in Niemann–Pick type C cells and in cells treated with amphiphiles. J. Biol. Chem. 275, 17468–17475 (2000).

  19. 19.

    Pharmacological inhibition of the intracellular transport of low-density lipoprotein-derived cholesterol in Chinese hamster ovary cells. Biochim. Biophys. Acta 1045, 40–48 (1990).

  20. 20.

    et al. The Niemann–Pick C lesion and its relationship to the intracellular distribution and utilization of LDL cholesterol. Biochim. Biophys. Acta 1225, 235–243 (1994).

  21. 21.

    , , , & Caveolae and sorting in the trans-Golgi network of epithelial cells. EMBO J. 12, 1597–1605 (1993).

  22. 22.

    et al. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl Acad. Sci. USA 92, 10339–10343 (1995).

  23. 23.

    , , & A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J. Biol. Chem. 271, 29427–29435 (1996).

  24. 24.

    & Traffic, polarity, and detergent solubility of a glycosylphosphatidylinositol-anchored protein after LDL-deprivation of MDCK cells. J. Cell Biol. 133, 1265–1276 (1996).

  25. 25.

    et al. Redistribution of glycolipid raft domain components induces insulin-mimetic signaling in rat adipocytes. Mol. Cell. Biol. 21, 4553–4567 (2001).

  26. 26.

    , & Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc. Natl Acad. Sci. USA 94, 10693–10698 (1997).

  27. 27.

    et al. Increased expression of caveolin-1 in heterozygous Niemann–Pick type II human fibroblasts. Biochem. Biophys. Res. Commun. 236, 189–193 (1997).

  28. 28.

    et al. Altered expression of caveolin-1 and increased cholesterol in detergent insoluble membrane fractions from liver in mice with Niemann–Pick disease type C. Biochim. Biophys. Acta 1361, 272–280 (1997).

  29. 29.

    et al. A caveolin dominant-negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance. J. Cell Biol. 152, 1057–1070 (2001).

  30. 30.

    , , , & Caveolin-2 is targeted to lipid droplets, a new 'membrane domain' in the cell. J. Cell Biol. 152, 1079–1085 (2001).References 29 and 30 describe the discovery of new membrane domains in cells, and their association with caveolin. Great morphological studies and excellent time-lapse microscopy.

  31. 31.

    & Functional rafts in cell membranes. Nature 387, 569–572 (1997).Proposes and demonstrates the existence of lipid rafts within the plasma membrane of mammalian cells.

  32. 32.

    , & van ABC transporters in lipid transport. Biochim. Biophys. Acta 1486, 128–144 (2000).

  33. 33.

    , & ABC transporters in cellular lipid trafficking. Curr. Opin. Lipidol. 11, 493–501 (2000).References 32 and 33 are excellent reviews on the involvement of ABC transporters in cellular lipid transport.

  34. 34.

    , & The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42, 1007–1017 (2001).

  35. 35.

    , & An inventory of the human ABC proteins. Biochim. Biophys. Acta 1461, 237–262 (1999).

  36. 36.

    , & Classification of all putative permeases and other membrane plurispanners of the major facilitator superfamily encoded by the complete genome of Saccharomyces cerevisiae. FEMS Microbiol. Rev. 21, 113–134 (1997).

  37. 37.

    et al. The pleiotropic drug ABC transporters from Saccharomyces cerevisiae. J. Mol. Microbiol. Biotechnol. 3, 207–214 (2001).

  38. 38.

    et al. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. FASEB J. 12, 265–274 (1998).

  39. 39.

    , & Antibiotic efflux pumps. Biochem. Pharmacol. 60, 457–470 (2000).

  40. 40.

    , , , & Mouse transporter protein, a membrane protein that regulates cellular multidrug resistance, is localized to lysosomes. Cancer Res. 59, 4890–4897 (1999).

  41. 41.

    , & Proton-dependent multidrug efflux systems. Microbiol. Rev. 60, 575–608 (1996).

  42. 42.

    et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 70, 539–551 (1992).

  43. 43.

    et al. Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7). Biochem. Biophys. Res. Commun. 273, 532–538 (2000).

  44. 44.

    Tangier disease and ABCA1. Biochim. Biophys. Acta 1529, 321–330 (2000).

  45. 45.

    et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nature Genet. 22, 347–351 (1999).

  46. 46.

    et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature Genet. 22, 336–345 (1999).

  47. 47.

    et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nature Genet. 22, 352–355 (1999).References 45–47 describe the molecular defect in Tangier disease, setting in motion an explosion in the field of ABC transporters and their involvement in lipid transport.

  48. 48.

    et al. Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations. Atherosclerosis 152, 457–468 (2000).

  49. 49.

    et al. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J. Clin. Invest. 106, 1263–1270 (2000).

  50. 50.

    , , & Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275, 28240–28245 (2000).

  51. 51.

    et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).

  52. 52.

    , , & Distantly related sequences in the α- and β-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1, 945–951 (1982).

  53. 53.

    , , & Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J. Biol. Chem. 275, 33053–33058 (2000).

  54. 54.

    , , , & Membrane lipid domains distinct from cholesterol/sphingomyelin-rich rafts are involved in the ABCA1-mediated lipid secretory pathway. J. Biol. Chem. 276, 3158–3166 (2001).

  55. 55.

    , , & ABCA1 functions as a cholesterol efflux regulatory protein. J. Biol. Chem. 276, 23742–23747 (2001).

  56. 56.

    et al. Type C Niemann–Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-drerived cholesterol processing. Biochim. Biophys. Acta 1096, 328–337 (1991).

  57. 57.

    et al. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 3611–3634 (McGraw–Hill, New York, 2001).

  58. 58.

    et al. Type C Niemann–Pick disease: a parallel loss of regulatory responses in both the uptake and esterification of low-density lipoprotein-derived cholesterol in cultured fibroblasts. J. Biol. Chem. 261, 16775–16780 (1986).

  59. 59.

    et al. Niemann–Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228–231 (1997).

  60. 60.

    et al. The genomic organization and polymorphism analysis of the human Niemann–Pick C1 gene. Biochem. Biophys. Res. Commun. 261, 493–498 (1999).

  61. 61.

    et al. NPC1 gene mutations in Japanese patients with Niemann–Pick disease type C. Hum. Genet. 105, 10–16 (1999).

  62. 62.

    et al. Niemann–Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am. J. Hum. Genet. 65, 1321–1329 (1999).

  63. 63.

    et al. Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am. J. Hum. Genet. 65, 1252–1260 (1999).

  64. 64.

    et al. The Nova Scotia (type D) form of NiemannPick disease is caused by a G3097→T transversion in NPC1. Am. J. Hum. Genet. 63, 52–54 (1998).

  65. 65.

    et al. Niemann–Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am. J. Hum. Genet. 68, 1361–1372 (2001).

  66. 66.

    et al. Niemann–Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am. J. Hum. Genet. 68, 1373–1385 (2001).

  67. 67.

    et al. Group C Niemann–Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J. 1, 40–45 (1987).

  68. 68.

    & Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann–Pick type C fibroblasts. J. Biol. Chem. 262, 17002–17008 (1987).

  69. 69.

    , & Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein-cholesterol trafficking. J. Cell Biol. 110, 295–308 (1990).

  70. 70.

    , , , & Isolation and characterization of Chinese hamster ovary cells defective in the intracellular metabolism of low density lipoprotein-derived cholesterol. J. Biol. Chem. 267, 4889–4896 (1992).

  71. 71.

    , & Transmembrane molecular pump activity of Niemann–Pick C1 protein. Science 290, 2295–2298 (2000).

  72. 72.

    , , , & Biochemical evidence that patched is the hedgehog receptor. Nature 384, 176–179 (1996).

  73. 73.

    et al. The tumour suppressor gene patched encodes a candidate receptor for sonic hedgehog. Nature 384, 129–133 (1996).

  74. 74.

    et al. The hedgehog gene family in Drosophila and vertebrate development. Dev. Suppl. 43–51 (1994).

  75. 75.

    et al. Autoproteolysis in hedgehog protein biogenesis. Science 266, 1528–1537 (1994).

  76. 76.

    , , & Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87, 415–426 (1996).

  77. 77.

    , & Evidence for a Niemann–Pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 65, 137–145 (2000).

  78. 78.

    et al. The Niemann–Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J. Biol. Chem. 274, 9627–9635 (1999).

  79. 79.

    et al. Localization of Niemann–Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann–Pick type C disease. Proc. Natl Acad. Sci. USA 96, 1657–1662 (1999).

  80. 80.

    , , & Niemann–Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol. Genet. Metab. 68, 1–13 (1999).

  81. 81.

    et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nature Cell Biol. 1, 113–118 (1999).The first report to establish the late endosome as the cholesterol storage compartment in NPC−/− cells and the role of lysobisphosphatidic acid in regulating cholesterol transport.

  82. 82.

    et al. Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nature Cell Biol. 1, 386–388 (1999).An excellent paper describing the involvement of cholesterol in the regulation of membrane transport.

  83. 83.

    , , & Dynamic movements of organelles containing Niemann–Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601–614 (2001).

  84. 84.

    et al. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease. Proc. Natl Acad. Sci. USA 98, 4466–4471 (2001).

  85. 85.

    et al. Sterol-modulated glycolipid sorting occurs in Niemann–Pick C1 late endosomes. J. Biol. Chem. 276, 3417–3425 (2001).

  86. 86.

    , , , & Niemann–Pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis. J. Biol. Chem. 275, 38445–38451 (2000).

  87. 87.

    , , & Cloning of cDNAs encoding human lysosomal membrane glycoproteins, h-lamp-1 and h-lamp-2. J. Biol. Chem. 262, 18920–18928 (1988).

  88. 88.

    et al. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1, 107–125 (1999).

  89. 89.

    , & Molecular cloning and characterization of HE1, a major secretory protein of the human epididymis. Biol. Reprod. 54, 847–856 (1996).

  90. 90.

    et al. Identification of HE1 as the second gene of Niemann–Pick C disease. Science 290, 2298–2301 (2000).Elucidation of the molecular defect in NPC type 2 disease.

  91. 91.

    et al. A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochim. Biophys. Acta 1438, 377–387 (1999).

  92. 92.

    & Ultrastructure appearance of atherosclerosis in human and experimentally-induced animal models. Electron Microsc. Rev. 5, 129–170 (1992).

  93. 93.

    et al. Formation of cholesterol monohydrate crystals in macrophage-derived foam cells. J. Lipid Res. 35, 93–104 (1994).

  94. 94.

    , , & Lysosome lipid storage disorder in NCTR-BALB/c mice. II. Morphologic and cytochemical studies. Am. J. Pathol. 108, 150–159 (1982).

  95. 95.

    et al. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11–q21.3 region of chromosome 17. Genomics 28, 367–376 (1995).

  96. 96.

    et al. MLN64 exhibits homology with the steroidogenic acute regulatory protein (STAR) and is over-expressed in human breast carcinomas. Int. J. Cancer 71, 183–191 (1997).

  97. 97.

    et al. MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc. Natl Acad. Sci. USA 94, 8462–8467 (1997).

  98. 98.

    & Structure and lipid transport mechanism of a StAR-related domain. Nature Struct. Biol. 7, 408–414 (2000).

  99. 99.

    et al. The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. J. Biol. Chem. 276, 4261–4269 (2001).

  100. 100.

    , , & Sterol regulatory binding element protein binds to cis element in the promoter of the farnesyl diphosphate gene. Proc. Natl Acad. Sci. USA 93, 945–950 (1996).

  101. 101.

    , & YY1 is a negative regulator of transcription of three sterol regulatory element-binding protein-responsive genes. J. Biol. Chem. 274, 14508–14513 (1999).

  102. 102.

    & An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res. 22, 5151–5155 (1994).

  103. 103.

    , , & Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).

  104. 104.

    , & Cholesterol modification of hedgehog signaling protein in animal development. Science 274, 255–259 (1996).An excellent paper, demonstrating the autoproteolysis and cholesterol modification of Hedghog protein.

  105. 105.

    , , Von , & The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 86, 221–232 (1996).

  106. 106.

    , , & The patched signaling pathway in tumorigenesis and development: lessons from animal models. J. Mol. Med. 77, 459–468 (1999).

  107. 107.

    et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

  108. 108.

    et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798–1803 (1998).

  109. 109.

    et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).

  110. 110.

    , , & The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking. Curr. Biol. 11, 601–607 (2001).

  111. 111.

    et al. Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Curr. Biol. 11, 608–613 (2001).

  112. 112.

    , & Metabolic fate of oleic acid derived from lysosomal degradation of cholesteryl oleate in human fibroblasts. J. Lipid Res. 37, 2271–2279 (1996).

  113. 113.

    & Mechanisms of cellular uptake of long chain free fatty acids. Mol. Cell Biochem. 192, 17–31 (1999).

  114. 114.

    Cellular uptake of long-chain fatty acids: role of membrane-associated fatty-acid-binding/transport proteins. Cell. Mol. Life Sci. 57, 1360–1372 (2000).

  115. 115.

    & Sticky-finger interaction sites on cytosolic lipid-binding proteins? Cell. Mol. Life Sci. 57, 1379–1387 (2000).

  116. 116.

    The cytoplasmic fatty-acid-binding proteins: thirty years and counting. Cell. Mol. Life Sci. 57, 1345–1359 (2000).

  117. 117.

    et al. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc. Natl Acad. Sci. USA 98, 6027–6032 (2001).

  118. 118.

    , , , & Polyunsaturated fatty acids suppress hepatic sterol regulatory element- binding protein-1 expression by accelerating transcript decay. J. Biol. Chem. 276, 9800–9807 (2001).

  119. 119.

    , , , & Unsaturated fatty acids down-regulate SREPB isoforms 1a and 1c by two mechanisms in HEK-293 cells. J. Biol. Chem. 276, 4365–4372 (2001).

  120. 120.

    , , & Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins. J. Biol. Chem. 273, 26138–26148 (1998).

  121. 121.

    et al. Lysosomal membrane cholesterol dynamics. Biochemistry 39, 7662–7677 (2000).A great study that demonstrates the requirement of processes extrinsic to the lysosomal membrane for efficient cholesterol exit from this compartment.

  122. 122.

    , & Neurons in Niemann–Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J. Neuropathol. Exp. Neurol. 60, 49–64 (2001).

  123. 123.

    & Quantified increases of cholesterol, total lipid and globotriaosylceramide in filipin-positive Niemann–Pick type C fibroblasts. Clin. Chim. Acta 305, 65–73 (2001).

  124. 124.

    , , & Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann–Pick type C cells. J. Biol. Chem. 276, 4454–4460 (2001).

  125. 125.

    & Jamming the endosomal system: lipid rafts and lysosomal storage diseases. Trends Cell Biol. 10, 459–462 (2000).

Download references

Acknowledgements

I apologize for the omission of many outstanding papers that could not be cited or discussed owing to space limitations.

Author information

Affiliations

  1. Departments of Human Genetics, Gene Therapy and Molecular Medicine, Box 1498, The Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029, USA. yiannis.ioannou@mssm.edu

    • Yiannis A. Ioannou

Authors

  1. Search for Yiannis A. Ioannou in:

Supplementary information

Glossary

LOW-DENSITY LIPOPROTEIN RECEPTOR

(LDLR). A plasma-membrane receptor found on most mammalian cells. Responsible for the salvaging of cholesterol from circulation through the endocytosis of LDL particles.

LIPOPROTEINS

Particles such as LDL and HDL, found in the blood circulation, which carry lipids from the liver to peripheral tissues and back. These particles have a hydrophobic core containing triglycerides and cholesterol esters surrounded by a phospholipid and protein coat, composed of different apolipoproteins.

CLATHRIN-COATED VESICLE

Vesicles that bud off the plasma membrane or the trans-Golgi network. They have a characteristic protein coat, made up of clathrin triskelions.

GLYCOSYLPHOSPHATIDYL-INOSITOL (GPI)-ANCHORED PROTEINS

Proteins found predominantly at the plasma membrane, attached to the lipid bilayer through a hydrophobic anchor, consisting of the two-fatty-acid-chain lipid, glycosylphosphatidylinositol.

STEROL REGULATORY ELEMENT

A consensus sequence found in the promoter regions of several genes. The element is recognized by specific transcription factors that stimulate transcription when cellular sterol or fatty acid levels are low.

HIGH-DENSITY LIPOPROTEIN PARTICLES

(HDLs). Differ from LDLs in the composition of their hydrophobic core and the apolipoprotein composition of their coat.

ABC-TYPE TRANSPORTER

A type of transport protein that contains a consensus sequence known as the ATP-binding cassette.

WALKER A AND WALKER B MOTIFS

Protein motifs that form the nucleotide-binding site of an ABC domain. Walker A has the consensus GE-VALVGPSGSGKSTLL and Walker B the consensus ILLLDEPTSALD. (bold amino acids are invariant.)

PERMEASE

A membrane transporter, also known as a carrier protein or a transporter.

ANTIPORTS, SYMPORTS AND UNIPORTS

Uniports transport their substrate across a membrane. Coupled transporters couple the transport of their substrate to the transfer of a second solute, either in the same direction (symports) or in the opposite direction (antiports).

PROTON-MOTIVE FORCE

(PMF). The force generated across a membrane by the unidirectional transport of protons across a membrane. Both the membrane potential Δψ and the pH gradient ΔpH can contribute to this force.

APOLIPOPROTEIN A-1 (APOA1)

One of the apolipoproteins found predominantly in the coat of HDL particles.

LIPIDOSIS

Storage of various lipids in the lysosomal system is the common phenotype for this group of lysosomal storage diseases.

HEPATOSPLENOMEGALY

An enlargement of the liver and spleen seen in several lysosomal storage diseases.

LAMP-POSITIVE ORGANELLES

Organelles that contain the lysosome-associated membrane protein. Labels lysosomes.

RAB7-POSITIVE

Organelles that contain Rab7, a small GTPase found predominantly in late endosomes.

BODIPY

Trade name for a family of fluorophores that span the visible spectrum, and are used to label proteins, nucleotides, lipids and other molecules.

PERINUCLEAR VESICLES

Vesicular structures that are seen surrounding the nucleus. Usually indicative of lysosomes.

MANNOSE 6-PHOSPHATE MODIFICATION

A phosphate modification of the carbohydrate moieties of proteins destined for the endosomal–lysosomal system. This modification is recognized by the mannose 6-phosphate receptor in the trans-Golgi network, which captures these proteins and transports them to late endosomes.

YIN–YANG-1-BINDING SITE

A consensus sequence found in the promoter region of several genes. In the context of a sterol regulatory element, it acts as a negative regulator of transcription.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/35089558

Further reading