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PMID: 20627678 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Cholesterol, the central lipid of mammalian cells.

Current opinion in cell biology ·Vol. 22 ·No. 4 ·2010-08-00 ·Pages 422-9

Maxfield FR, van Meer G

Abstract

Despite its importance for mammalian cell biology and human health, there are many basic aspects of cholesterol homeostasis that are not well understood. Even for the well-characterized delivery of cholesterol to cells via lipoproteins, a novel regulatory mechanism has been discovered recently, involving a serum protein called PCSK9, which profoundly affects lipoproteins and their receptors. Cells can export cholesterol by processes that require the activity of ABC transporters, but the molecular mechanisms for cholesterol transport remain unclear. Cholesterol levels in different organelles vary by 5-10-fold, and the mechanisms for maintaining these differences are now partially understood. Several proteins have been proposed to play a role in the inter-organelle movement of cholesterol, but many aspects of the mechanisms for regulating intracellular transport and distribution of cholesterol remain to be worked out. The endoplasmic reticulum is the main organelle responsible for regulation of cholesterol synthesis, and careful measurements have shown that the proteins responsible for sterol sensing respond over a very narrow range of cholesterol concentrations to provide very precise, switch-like control over cholesterol synthesis.

MeSH Terms
Animals Cell Membrane/metabolism Cells/metabolism Cholesterol/metabolism Homeostasis Humans Mammals/metabolism
Chemicals
Cholesterol
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Maxfield Frederick R
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. [email protected]
van Meer Gerrit
References (72)
72 references, click to expand
  1. Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid.
    J Lipid Res. 2010 May;51(5):933-44 PMID: 19965601
  2. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants.
    J Biol Chem. 2009 Jan 9;284(2):1313-23 PMID: 19001363
  3. Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption.
    J Lipid Res. 2009 Nov;50(11):2235-44 PMID: 19454765
  4. Seeing spots: complex phase behavior in simple membranes.
    Biochim Biophys Acta. 2005 Dec 30;1746(3):172-85 PMID: 16043244
  5. Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop.
    J Biol Chem. 2008 Jan 11;283(2):1064-75 PMID: 17989072
  6. Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain.
    Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12473-8 PMID: 15314240
  7. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.
    J Biol Chem. 2007 Jun 22;282(25):18602-18612 PMID: 17452316
  8. Transmembrane passage of hydrophobic compounds through a protein channel wall.
    Nature. 2009 Mar 19;458(7236):367-70 PMID: 19182779
  9. Lipid polarity and sorting in epithelial cells.
    J Cell Biochem. 1988 Jan;36(1):51-8 PMID: 3277985
  10. Endocytic sorting of lipid analogues differing solely in the chemistry of their hydrophobic tails.
    J Cell Biol. 1999 Mar 22;144(6):1271-84 PMID: 10087269
  11. ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse.
    J Lipid Res. 2009 Jul;50(7):1316-29 PMID: 19286647
  12. OSBP is a cholesterol-regulated scaffolding protein in control of ERK 1/2 activation.
    Science. 2005 Mar 4;307(5714):1472-6 PMID: 15746430
  13. Regulated endoplasmic reticulum-associated degradation of a polytopic protein: p97 recruits proteasomes to Insig-1 before extraction from membranes.
    J Biol Chem. 2009 Dec 11;284(50):34889-900 PMID: 19815544
  14. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.
    Am J Hum Genet. 2006 Sep;79(3):514-23 PMID: 16909389
  15. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.
    Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1615-21 PMID: 19556523
  16. Purified NPC1 protein. I. Binding of cholesterol and oxysterols to a 1278-amino acid membrane protein.
    J Biol Chem. 2008 Jan 11;283(2):1052-63 PMID: 17989073
  17. Condensed complexes in vesicles containing cholesterol and phospholipids.
    Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12662-6 PMID: 16120676
  18. The OSBP-related proteins: a novel protein family involved in vesicle transport, cellular lipid metabolism, and cell signalling.
    Biochim Biophys Acta. 2003 Feb 20;1631(1):1-11 PMID: 12573443
  19. The BAR domain superfamily: membrane-molding macromolecules.
    Cell. 2009 Apr 17;137(2):191-6 PMID: 19379681
  20. A glycophospholipid membrane anchor acts as an apical targeting signal in polarized epithelial cells.
    J Cell Biol. 1989 Nov;109(5):2145-56 PMID: 2478564
  21. Give lipids a START: the StAR-related lipid transfer (START) domain in mammals.
    J Cell Sci. 2005 Jul 1;118(Pt 13):2791-801 PMID: 15976441
  22. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning.
    J Cell Biol. 2009 Jun 29;185(7):1209-25 PMID: 19564404
  23. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.
    Cell. 2009 Jun 26;137(7):1213-24 PMID: 19563754
  24. Sorting of lipids and proteins in membrane curvature gradients.
    Biophys J. 2009 Apr 8;96(7):2676-88 PMID: 19348750
  25. Membrane lipids: where they are and how they behave.
    Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24 PMID: 18216768
  26. Quantitative analysis of phospholipids in functionally important membrane domains from RBL-2H3 mast cells using tandem high-resolution mass spectrometry.
    Biochemistry. 1999 Jun 22;38(25):8056-63 PMID: 10387050
  27. The OSBP-related proteins (ORPs): global sterol sensors for co-ordination of cellular lipid metabolism, membrane trafficking and signalling processes?
    Biochem Soc Trans. 2006 Jun;34(Pt 3):389-91 PMID: 16709169
  28. Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells.
    Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19316-21 PMID: 19884502
  29. The LDL receptor.
    Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):431-8 PMID: 19299327
  30. Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologues.
    J Cell Biol. 2009 Dec 14;187(6):889-903 PMID: 20008566
  31. The pathophysiology and mechanisms of NP-C disease.
    Biochim Biophys Acta. 2004 Oct 11;1685(1-3):83-7 PMID: 15465429
  32. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain.
    Mol Cell. 2004 Jul 23;15(2):259-68 PMID: 15260976
  33. CERT mediates intermembrane transfer of various molecular species of ceramides.
    J Biol Chem. 2005 Feb 25;280(8):6488-95 PMID: 15596449
  34. The lipidomes of vesicular stomatitis virus, semliki forest virus, and the host plasma membrane analyzed by quantitative shotgun mass spectrometry.
    J Virol. 2009 Aug;83(16):7996-8003 PMID: 19474104
  35. Crosslinking a lipid raft component triggers liquid ordered-liquid disordered phase separation in model plasma membranes.
    Proc Natl Acad Sci U S A. 2005 May 3;102(18):6320-5 PMID: 15851688
  36. Oligomerized transferrin receptors are selectively retained by a lumenal sorting signal in a long-lived endocytic recycling compartment.
    J Cell Biol. 1995 Jun;129(6):1509-22 PMID: 7790351
  37. Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol.
    Prog Lipid Res. 2008 Sep;47(5):319-32 PMID: 18423408
  38. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis.
    J Intern Med. 2009 Dec;266(6):507-19 PMID: 19930098
  39. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells.
    J Biol Chem. 2007 Jul 20;282(29):20799-803 PMID: 17537735
  40. Metabolic innovations towards the human lineage.
    BMC Evol Biol. 2008 Sep 09;8:247 PMID: 18782449
  41. Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity.
    Biochem J. 2007 Sep 1;406(2):203-7 PMID: 17608623
  42. Phylogenomics of sterol synthesis: insights into the origin, evolution, and diversity of a key eukaryotic feature.
    Genome Biol Evol. 2009 Sep 10;1:364-81 PMID: 20333205
  43. Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter.
    Biochim Biophys Acta. 2009 Jul;1791(7):679-83 PMID: 19272334
  44. Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression.
    Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1723-30 PMID: 18669882
  45. PCSK9: a convertase that coordinates LDL catabolism.
    J Lipid Res. 2009 Apr;50 Suppl:S172-7 PMID: 19020338
  46. Oxysterol binding protein-related Protein 9 (ORP9) is a cholesterol transfer protein that regulates Golgi structure and function.
    Mol Biol Cell. 2009 Mar;20(5):1388-99 PMID: 19129476
  47. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.
    PLoS One. 2009 Sep 11;4(9):e6951 PMID: 19750228
  48. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.
    Cell Metab. 2008 May;7(5):365-75 PMID: 18460328
  49. Intracellular sterol dynamics.
    Biochim Biophys Acta. 2009 Jul;1791(7):636-45 PMID: 19286471
  50. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance.
    Cell Metab. 2008 Dec;8(6):512-21 PMID: 19041766
  51. Sterols are mainly in the cytoplasmic leaflet of the plasma membrane and the endocytic recycling compartment in CHO cells.
    Mol Biol Cell. 2009 Jan;20(2):581-8 PMID: 19019985
  52. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells.
    Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5477-82 PMID: 20212119
  53. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion.
    J Biol Chem. 2003 Nov 28;278(48):48275-82 PMID: 14504269
  54. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration.
    Biochemistry. 2005 Apr 19;44(15):5816-26 PMID: 15823040
  55. Oxysterol-binding protein and vesicle-associated membrane protein-associated protein are required for sterol-dependent activation of the ceramide transport protein.
    Mol Biol Cell. 2006 Jun;17(6):2604-16 PMID: 16571669
  56. Measurement of the membrane curvature preference of phospholipids reveals only weak coupling between lipid shape and leaflet curvature.
    Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22245-50 PMID: 20080790
  57. Role of curvature and phase transition in lipid sorting and fission of membrane tubules.
    EMBO J. 2005 Apr 20;24(8):1537-45 PMID: 15791208
  58. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.
    Mol Biol Cell. 2009 Dec;20(23):4932-40 PMID: 19812252
  59. Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation.
    J Lipid Res. 2008 Jul;49(7):1409-19 PMID: 18403318
  60. Clustering and lateral concentration of raft lipids by the MAL protein.
    Mol Biol Cell. 2009 Aug;20(16):3751-62 PMID: 19553470
  61. Structure and lipid transport mechanism of a StAR-related domain.
    Nat Struct Biol. 2000 May;7(5):408-14 PMID: 10802740
  62. Segregation of sphingolipids and sterols during formation of secretory vesicles at the trans-Golgi network.
    J Cell Biol. 2009 May 18;185(4):601-12 PMID: 19433450
  63. Self-association of human PCSK9 correlates with its LDLR-degrading activity.
    Biochemistry. 2008 Feb 12;47(6):1631-9 PMID: 18197702
  64. Phase diagrams and lipid domains in multicomponent lipid bilayer mixtures.
    Biochim Biophys Acta. 2009 Jan;1788(1):47-52 PMID: 18805392
  65. Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease.
    J Biol Chem. 2007 Aug 10;282(32):23525-31 PMID: 17573352
  66. Regulation of sterol transport between membranes and NPC2.
    Biochemistry. 2008 Oct 21;47(42):11134-43 PMID: 18823126
  67. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes.
    Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15287-92 PMID: 18772377
  68. Curvature-driven lipid sorting needs proximity to a demixing point and is aided by proteins.
    Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5622-6 PMID: 19304798
  69. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.
    Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13045-50 PMID: 18753623
  70. Cholesterol-induced fluid membrane domains: a compendium of lipid-raft ternary phase diagrams.
    Biochim Biophys Acta. 2009 Oct;1788(10):2114-23 PMID: 19699712
  71. OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids.
    J Lipid Res. 2009 Jul;50(7):1305-15 PMID: 19224871
  72. Evidence for segregation of sphingomyelin and cholesterol during formation of COPI-coated vesicles.
    J Cell Biol. 2000 Oct 30;151(3):507-18 PMID: 11062253
Article Info
Journal
Current opinion in cell biology
Abbr.
Curr Opin Cell Biol
ISSN
1879-0410
DOI
10.1016/j.ceb.2010.05.004
Email
[email protected]
Published
2010-08-00
Epub
2010-00-02
Pages
422-9
Language
English
Region
England
NLM ID
8913428
PMCID
PMC2910236
Subset
IM
Grants
NHLBI NIH HHS · R01 HL093324 · United States
NIDDK NIH HHS · R37 DK027083 · United States
NIDDK NIH HHS · R37 DK027083-32 · United States
External Links
PubMed source DOI: 10.1016/j.ceb.2010.05.004 PMC Full Text View journal details
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