Pathway Map Details

Cholesterol and Sphingolipids transport / Transport from Golgi and ER to the apical membrane (normal and CF)



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Object list (links open in MetaCore):

CETP, Sphingolipids plasma membrane, Caveolin-1, Sphingolipids vesicle, PLEKHA3 (FAPP1), Caveolin-1, CES1, Cholesterol cytoplasm, FKBP4, VIP36, PLEKHA8 (FAPP2), Sphingomyelin, Cholesterol endoplasmic reticulum membrane, Cyclophilin D, Cholesterol Golgi membrane, SMS1, Ceramide Golgi, ACAT1, Sphingolipids = Sphingolipids, Cholesteryl esters cytosol, Cholesterol plasma membrane inner leaflet, Cholesterol plasma membrane outer leaflet, ABCA1, Cholesteryl ester endoplasmic reticulum, ARF1, Cholesterol = Cholesterol, 2.3.1.9, 2.7.8.27, CERT, Sphingolipids = Sphingolipids, Ceramide endoplasmic reticulum lumen, Cholesterol = Cholesterol, Cholesterol vesicle, Caveolin-1, Cholesterol = Cholesterol, Sphingolipids Golgi, SCPX(SCP2), Cholesterol vesicle, Coatomer, Sphingolipids vesicle, Cyclophilin A, 3.1.1.13, Ceramide = Ceramide, Ceramide, Cholesteryl ester = Cholesteryl ester

Description:

Cholesterol and Sphingolipid transport/ Transport from Golgi and ER to the apical membrane (normal and CF)

CF pathway (highlighted in purple on map)

Increased Cholesterol and Sphingolipids in punctate endosomal structures indicates a block in the translocation of Cholesterol from endosomes and lysosomes to the endoplasmic reticulum (ER). The block prevents Cholesterol esterification and storage in the lipid droplets [1]. Decreased Cholesterol in ER produces the signal leading to increase in Cholesterol biosynthesis [2] and possibly acceleration of the ER-to-Golgi traffic [3], [4]. Treatment with the HMG-CoA reductase ( Cholesterol rate-limiting enzyme) inhibitor lovastatin reduced CFTR-mediated chloride transport and CFTR trafficking to the apical membrane [5]. An indirect marker of increased de novo Cholesterol synthesis is increased plasma membrane Cholesterol content in CF cells and tissues determined by electrochemical measurement [3], [6]. The effect of lovastatin raises the possibility that alteration in Cholesterol processing in CF cells is the adaptive cellular response to increase CFTR content in the plasma membrane [3].

Normal pathway

Most of de novo-synthesized Cholestero l in the ER is transported directly to the plasma membrane (PM) by a non-vesicular processes. Relatively small amounts of Cholesterol and de novo synthesized Sphingomyelin are transported from the ER to Golgi, and then to the plasma membrane. Non-vesicular transport from ER to PM proceeds via cytosolic FK506 binding protein 4 ( FKBP4 ) and Caveolin-1 containing complex [7], [8].

Excessive Cholesterol in the ER is esterified by acetyl-Coenzyme A acetyltransferase 1 ( ACAT1 ) and the esters are stored in cytoplasmic lipid droplets [9]. Cholesteryl ester transfer protein ( CETP ) transports Cholesteryl ester into storage droplets [10]. Fraction of lipid droplets that contains CES1 increases in response to dietary Cholesterol supply [11].

ER ACAT1 is compartmentalized close to the ERC and very close to TGN, but farther from cis, medial, and trans Golgi. Since both Trans-Golgi network (TGN) and Endocytic recycling compartment (ERC) are engaged in extensive membrane traffic, esterification of Cholesterol in these membranes may play an important role [12].

Lipid vesicle retrograde pathway from Golgi to ER is still being investigated, but probably Cholesterol and other raft lipids are excluded from such traffic [13].

Lipid rafts, caveolae or transport vesicles that contain Cholesterol/Sphingolipids -rich membrane patches are formed in TGN [14]. Lectin, mannose-binding 2 protein ( VIP 36 ) is one of the proteins coordinating polar traffic of caveolae to the PM [15], [16], [17]. These proteins receive Sphingolipids and Cholesterol from carriers, endosomes, lipid droplets or ER. The pool of Sphingolipids is enriched by Sphingomyelin that is newly synthesized by sphingomyelin synthase 1 ( SMS1 ). These lipid-rich structures move to the apical plasma membrane [16], [18], [14]. Unlike Cholesterol, Sphingomyelin is transported to the apical membrane preferentially in the vesicles [19].

Soluble cytosolic proteins such as sterol carrier protein 2 ( SCPX(SCP2) ) promote Cholesterol non-vesicle transport between intracellular membranes (endosomes, lysosome, endoplasmic reticulum (ER), complex Golgi etc.), cytosolic Cholesterol/Cholesteryl ester pool (lipid droplets) and probably to inner leaflet of plasma membrane [20], [21], [22], [23], [24].

Soluble cytosolic sterol carrier proteins transport Cholesterol to the inner leaflet of PM. ATP-binding cassette family member 1 ( ABCA1 ) transports Cholestero l from inner to outer leaflets [25], [26], [27].

References:

  1. Gentzsch M, Choudhury A, Chang XB, Pagano RE, Riordan JR
    Misassembled mutant DeltaF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. Journal of cell science 2007 Feb 1;120(Pt 3):447-55
  2. Bengoechea-Alonso MT, Ericsson J
    SREBP in signal transduction: cholesterol metabolism and beyond. Current opinion in cell biology 2007 Feb 13;
  3. White NM, Jiang D, Burgess JD, Bederman IR, Previs SF, Kelley TJ
    Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis. American journal of physiology. Lung cellular and molecular physiology 2007 Feb;292(2):L476-86
  4. Ikonen E
    Cellular cholesterol trafficking and compartmentalization. Nature reviews. Molecular cell biology 2008 Feb;9(2):125-38
  5. Shen BQ, Widdicombe JH, Mrsny RJ
    Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium. The Journal of biological chemistry 1995 Oct 20;270(42):25102-6
  6. Jiang D, Fang D, Kelley TJ, Burgess JD
    Electrochemical analysis of cell plasma membrane cholesterol at the airway surface of mouse trachea. Analytical chemistry 2008 Feb 15;80(4):1235-9
  7. Uittenbogaard A, Ying Y, Smart EJ
    Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. Involvement in cholesterol trafficking. The Journal of biological chemistry 1998 Mar 13;273(11):6525-32
  8. Holtta-Vuori M, Ikonen E
    Endosomal cholesterol traffic: vesicular and non-vesicular mechanisms meet. Biochemical Society transactions 2006 Jun;34(Pt 3):392-4
  9. Liu J, Chang CC, Westover EJ, Covey DF, Chang TY
    Investigating the allosterism of acyl-CoA:cholesterol acyltransferase (ACAT) by using various sterols: in vitro and intact cell studies. The Biochemical journal 2005 Oct 15;391(Pt 2):389-97
  10. Izem L, Morton RE
    Possible role for intracellular cholesteryl ester transfer protein in adipocyte lipid metabolism and storage. The Journal of biological chemistry 2007 Jul 27;282(30):21856-65
  11. Zhao B, Fisher BJ, St Clair RW, Rudel LL, Ghosh S
    Redistribution of macrophage cholesteryl ester hydrolase from cytoplasm to lipid droplets upon lipid loading. Journal of lipid research 2005 Oct;46(10):2114-21
  12. Khelef N, Soe TT, Quehenberger O, Beatini N, Tabas I, Maxfield FR
    Enrichment of acyl coenzyme A:cholesterol O-acyltransferase near trans-golgi network and endocytic recycling compartment. Arteriosclerosis, thrombosis, and vascular biology 2000 Jul;20(7):1769-76
  13. Fullekrug J, Simons K
    Lipid rafts and apical membrane traffic. Annals of the New York Academy of Sciences 2004 Apr;1014:164-9
  14. Tagawa A, Mezzacasa A, Hayer A, Longatti A, Pelkmans L, Helenius A
    Assembly and trafficking of caveolar domains in the cell: caveolae as stable, cargo-triggered, vesicular transporters. The Journal of cell biology 2005 Aug 29;170(5):769-79
  15. Fiedler K, Parton RG, Kellner R, Etzold T, Simons K
    VIP36, a novel component of glycolipid rafts and exocytic carrier vesicles in epithelial cells. The EMBO journal 1994 Apr 1;13(7):1729-40
  16. Heino S, Lusa S, Somerharju P, Ehnholm C, Olkkonen VM, Ikonen E
    Dissecting the role of the golgi complex and lipid rafts in biosynthetic transport of cholesterol to the cell surface. Proceedings of the National Academy of Sciences of the United States of America 2000 Jul 18;97(15):8375-80
  17. Cubells L, Vila de Muga S, Tebar F, Wood P, Evans R, Ingelmo-Torres M, Calvo M, Gaus K, Pol A, Grewal T, Enrich C
    Annexin A6-Induced Alterations in Cholesterol Transport and Caveolin Export from the Golgi Complex. Traffic (Copenhagen, Denmark) 2007 Oct 15;8(11):1568-1589
  18. Godi A, Di Campli A, Konstantakopoulos A, Di Tullio G, Alessi DR, Kular GS, Daniele T, Marra P, Lucocq JM, De Matteis MA
    FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P. Nature cell biology 2004 May;6(5):393-404
  19. Boehm S
    Selective inhibition of M-type potassium channels in rat sympathetic neurons by uridine nucleotide preferring receptors. British journal of pharmacology 1998 Jul;124(6):1261-9
  20. Wustner D, Herrmann A, Hao M, Maxfield FR
    Rapid nonvesicular transport of sterol between the plasma membrane domains of polarized hepatic cells. The Journal of biological chemistry 2002 Aug 16;277(33):30325-36
  21. Rodriguez-Agudo D, Ren S, Hylemon PB, Montanez R, Redford K, Natarajan R, Medina MA, Gil G, Pandak WM
    Localization of StarD5 cholesterol binding protein. Journal of lipid research 2006 Jun;47(6):1168-75
  22. Miller WL
    Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochimica et biophysica acta 2007 Jun;1771(6):663-76
  23. de Donato G, Gussoni G, de Donato G, Cao P, Setacci C, Pratesi C, Mazzone A, Ferrari M, Veglia F, Bonizzoni E, Settembrini P, Ebner H, Martino A, Palombo D
    Acute limb ischemia in elderly patients: can iloprost be useful as an adjuvant to surgery? Results from the ILAILL study. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery 2007 Aug;34(2):194-8
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    Non-vesicular sterol transport in cells. Progress in lipid research 2007 Nov;46(6):297-314
  25. Chen W, Sun Y, Welch C, Gorelik A, Leventhal AR, Tabas I, Tall AR
    Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes. The Journal of biological chemistry 2001 Nov 23;276(47):43564-9
  26. Gadsby DC, Vergani P, Csanady L
    The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006 Mar 23;440(7083):477-83
  27. Ghering AB, Davidson WS
    Ceramide structural features required to stimulate ABCA1-mediated cholesterol efflux to apolipoprotein A-I. Journal of lipid research 2006 Dec;47(12):2781-8