Pathway Map Details

Cholesterol and Sphingolipids transport / Influx to the early endosome in lung (normal and CF)



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Object list (links open in MetaCore):

Sphingomyelin = Sphingomyelin, Sphingolipids, lLDL = cholesterol + cholesteryl ester + phospholipid, Rab-4, IDL lipids, lIDL = triacylglycerols + cholesteryl ester + phospholipid, Rab-5A, LDL lipids, Sphingomyelin plasma membrane, Cholesteryl ester vesicle, Sphingomyelin = Sphingomyelin, lLDL = lLDL, ARH, Glycosphingolipid plasma membrane, Clathrin, Caveolin-1, DAB2, LDL lipids, Caveolin-2, AP complex 2, Glycosphingolipid = Glycosphingolipid, IDL lipids, Cholesterol extracellular region, LDLR, Cholesteryl ester extracellular region, Cholesterol vesicle, Dynamin-2, Sphingomyelin, lIDL = lIDL, Rabenosyn-5, Glycosphingolipid cytoplasm

Description:

Cholesterol and Sphingolipid transport/ Influx to the early endosome in lung (normal and CF)

Lung cells absorb Cholesterol preferentially as Cholesteryl ester bound to lipoprotein particles such as Intermediate density lipoproteins ( IDL ) and Low density lipoproteins ( LDL ) [1]. These lipoproteins are recognized by corresponding low density lipoprotein receptor ( LDLR ) [2], [1], [3], [4]. LDLR is internalized into clathrin-coated pits and transported to sorting endosomes. Disabled homolog 2 ( Dab2 ) protein mediates internalization of Low density lipoprotein receptor ( LDLR ) independently of LDL receptor adaptor protein 1 ( ARH ) and the Adaptor-related protein complex 2 ( AP-2 ). If Dab2 is absent, ARH can mediate LDLR endocytosis. This mediation requires AP complex 2 [5], [6].

Sphingolipid -containing membranes are internalized via the caveolae-raft or clathrin-dependent pathways that involve Caveolin-1 [7].

Further lipid sorting from early endosomes to sorting endosomes is mediated by members of the RAS oncogene family Rab-5A and Rab-4 in clathrin vesicles formed from pits. Rab-5 -independent sorting also occurs in caveolae endosomes [8].

References:

  1. Kwiterovich PO Jr
    The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review. The American journal of cardiology 2000 Dec 21;86(12A):5L-10L
  2. Truong TQ, Falstrault L, Tremblay C, Brissette L
    Low density lipoprotein-receptor plays a major role in the binding of very low density lipoproteins and their remnants on HepG2 cells. The international journal of biochemistry & cell biology 1999 Jun;31(6):695-705
  3. Michaely P, Zhao Z, Li WP, Garuti R, Huang LJ, Hobbs HH, Cohen JC
    Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR. The EMBO journal 2007 Jul 25;26(14):3273-82
  4. Tall AR
    Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. Journal of internal medicine 2008 Mar;263(3):256-73
  5. Keyel PA, Mishra SK, Roth R, Heuser JE, Watkins SC, Traub LM
    A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Molecular biology of the cell 2006 Oct;17(10):4300-17
  6. Maurer ME, Cooper JA
    The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH. Journal of cell science 2006 Oct 15;119(Pt 20):4235-46
  7. Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, Marks DL, Pagano RE
    Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. The Journal of clinical investigation 2002 Jun;109(12):1541-50
  8. Sharma DK, Choudhury A, Singh RD, Wheatley CL, Marks DL, Pagano RE
    Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. The Journal of biological chemistry 2003 Feb 28;278(9):7564-72