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, 18.104.22.168, 22.214.171.124, 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, 126.96.36.199, <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 . Decreased Cholesterol in ER produces the signal leading to increase in Cholesterol biosynthesis  and possibly acceleration of the ER-to-Golgi traffic , . Treatment with the HMG-CoA reductase ( Cholesterol rate-limiting enzyme) inhibitor lovastatin reduced CFTR-mediated chloride transport and CFTR trafficking to the apical membrane . An indirect marker of increased de novo Cholesterol synthesis is increased plasma membrane Cholesterol content in CF cells and tissues determined by electrochemical measurement , . 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 .
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 , .
Excessive Cholesterol in the ER is esterified by acetyl-Coenzyme A acetyltransferase 1 ( ACAT1 ) and the esters are stored in cytoplasmic lipid droplets . Cholesteryl ester transfer protein ( CETP ) transports Cholesteryl ester into storage droplets . Fraction of lipid droplets that contains CES1 increases in response to dietary Cholesterol supply .
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 .
Lipid vesicle retrograde pathway from Golgi to ER is still being investigated, but probably Cholesterol and other raft lipids are excluded from such traffic .
Lipid rafts, caveolae or transport vesicles that contain Cholesterol/Sphingolipids -rich membrane patches are formed in TGN . Lectin, mannose-binding 2 protein ( VIP 36 ) is one of the proteins coordinating polar traffic of caveolae to the PM , , . 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 , , . Unlike Cholesterol, Sphingomyelin is transported to the apical membrane preferentially in the vesicles .
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 , , , , .
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 , , .