Pathway maps

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

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, <Golgi apparatus> Sphingolipids = <vesicle> Sphingolipids, Cholesteryl esters cytosol, Cholesterol plasma membrane inner leaflet, Cholesterol plasma membrane outer leaflet, ABCA1, Cholesteryl ester endoplasmic reticulum, ARF1, <Golgi apparatus> Cholesterol = <vesicle> Cholesterol,,, CERT, <vesicle> Sphingolipids = <extracellular region> Sphingolipids, Ceramide endoplasmic reticulum lumen, <vesicle> Cholesterol = <plasma membrane> Cholesterol, Cholesterol vesicle, Caveolin-1, <cytoplasm> Cholesterol = <plasma membrane> Cholesterol, Sphingolipids Golgi, SCPX(SCP2), Cholesterol vesicle, Coatomer, Sphingolipids vesicle, Cyclophilin A,, <endoplasmic reticulum> Ceramide = <Golgi apparatus> Ceramide, Ceramide, <endoplasmic reticulum> Cholesteryl ester = <cytosol> Cholesteryl ester


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].


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