Pathway maps

Cholesterol and Sphingolipids transport / Generic schema (normal and CF)
Cholesterol and Sphingolipids transport / Generic schema (normal and CF)

Object List (links open in MetaCore):

Cholesterol vesicle,,, Cholesterol outer leaflet, NPC1, Cholesterol Golgi membrane, NPC2,, Cholesterol extracellular region, Sphingolipids,, Sphingolipids TGN, Cholesteryl esters cytosol, Cholesterol TGN membrane,, Cholesteryl ester extracellular region, Sphingolipids vesicle, Cholesteryl ester endoplasmic reticulum, Cholesteryl ester vesicle, Cholesterol endoplasmic reticulum, Cholesterol inner leaflet, Cholesteryl ester lysosome, Sphingolipids, Sphingolipids plasma membrane, Cholesterol vesicle, Sphingolipids vesicle, Sphingolipids vesicle, Cholesteryl ester vesicle, Cholesterol plasma membrane, Cholesterol plasma membrane , Sphingolipids Golgi membrane, Cholesterol lysosome, Cholesterol cytoplasm, Cholesterol mitochondrial, Cholesterol vesicle, Cholesterol vesicle, Sphingolipids plasma membrane


Cholesterol and Sphingolipid transport/ Generic scheme (normal and CF)

CF pathway (highlighted in purple on map)

Cultured models of CF epithelial cells show intracellular accumulation of unesterified Cholesterol in a manner similar to Niemann-Pick disease and resulting in free Cholesterol accumulation in late endosomes and lysosomes [1], [2], [3]. Increased Cholesterol and Sphingolipids in punctate endosomal structures indicates a block in the translocation of Cholesterol to the ER. It prevents Cholesterol esterification and store in the lipid droplets [2]. Also it prevents Cholesterol biosynthesis inhibition and promotes Cholesterol biosynthesis de novo and ER-to-Golgi vesicle traffic [1], [4], [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 [1], [6]. Rab-9 overexpression clears the punctate Cholesterol accumulations, and this might be the consequence of Rab-9 overcoming an endosome-to-Golgi Cholesterol trafficking block in C F cells [2]. For instance, 3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor lovastatin reduces cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7) (CFTR)-mediated chloride transport and CFTR trafficking to the apical membrane [7]. Alterations in Cholesterol processing in CF cells may be viewed as an adaptive mechanism for increasing the content of CFTR at the plasma membrane [1].

Normal pathway

Cholesterol and Cholesteryl ester bound to lipoprotein particles are recognized by the corresponding receptors [8], [9], [10], [11]. Cholesterol receptors are selected for internalization into clathrin-coated pits and transported to sorting endosomes. Sphingolipid -containing membranes are internalized via caveolae-raft or clathrin-dependent pathways [12].

Internalized in early endosomes, High density lipoprotein ( HDL)-Cholestryl ester is hydrolyzed there by neutral cholesteryl ester hydrolase, unlike low density lipoprotein LDL-Cholesteryl ester [13], [14]. Further lipid sorting from early endosomes to sorting endosomes is mediated by members of the RAS oncogene family in in both clathrin pits and vesicles. Rab-independent sorting also occurs in caveolae endosomes [15].

Lipids return to the cell surface via a conventional, tubulo-vesicular membrane recycling pathway. In contrast, Cholesterol can move from the plasma membrane to the ERC by a non-vesicular, ATP-independent process. Soluble cytosolic proteins carry Cholestero l from internal membranes to plasmalemma, specifically to caveolae-lipid rafts [16], [17], [18]. As a result, ERC is one of the most Cholesterol -rich compartments in the cell [19].

Cholesterol can be transported from early to late endosomes and late endosomes to lysosomes. Rab-9 is believed to regulate the late step of Cholesterol transport from endosomes to the trans -Golgi network (TGN) [19]. Sphingolipids are sorted preferentially to TGN [12], but Cholesterol and, especially, Cholesteryl ester can be sorted to TGN and to lysosome. In lysosomes, acid cholesterol esterase hydrolyses Cholesteryl ester to free Cholesterol and fatty acids [20]. Sphingolipid activator proteins promote Sphingolipids degradation by lysosomal enzymes [21].

Exchange of Cholestrol content between late endosomes and lysosomes depends upon the ongoing tubulovesicular late endocytic trafficking. Tubulovesicular traffic not only mediates Cholesterol efflux from the late endosome membrane inner leaflet to the outer leaflet, but also promotes formation of tubules with Cholesterol from lysosomes and late endosomes toward other intracellular membranes especially trans-Golgi network (TGN) [22], [23], [24], [25].

Niemann-Pick disease, type C1 and C2 proteins ( NPC1 and NPC2 ) promote Cholesterol efflux presumably via direct interaction with the acceptor membrane. Transfer of Cholesterol to membranes is accelerated in the acidic environment [26].

StAR-related lipid transfer domain containing proteins may capture Cholesterol via their MENTAL domain in the late-endosomal membranes, and then Cholesterol can be transferred to the cytosolic acceptor protein or the membrane. Cholesterol transfer from other donor to acceptor vesicles has been shown to involve proteins with the START domain. [27], [28], [25].

Soluble cytosolic proteins like sterol promote Cholesterol transfer from the lysosome membrane to the outer mitochondrial membrane [29]. Thus, these proteins promote non-vesicle intracellular Cholesterol transport between intracellular membranes (endosomes, lysosome, endoplasmic reticulum (ER), complex Golgi etc.), cytosolic Chiolesterol/Cholesteryl ester pool, lipid droplets, and probably to the inner leaflet of plasma membrane [30], [31], [28], [32], [25].

Lipid rafts, caveolae or transport vesicles containing Cholesterol/Sphingolipids -rich membrane patches are formed in TGN. TGN receives Sphingolipids and Cholesterol from carriers, endosomes, lipid droplets, or ER. Pool of Sphingolipids is enriched by newly synthesized sphingomyelin. These lipid-rich structures move to the apical plasma membrane [33], [34], [35]. Unlike Cholesterol, Sphingomyelin is transported to the apical membrane preferentially by vesicles [36].

De novo-synthesized Cholestero l in the ER is transported directly to the PM by non-vesicular processes. However, some cholesterol and de novo synthesized Sphingomyelin follow the pathway from the ER to the Golgi and then to the plasma membrane. Non-vesicular transport from ER to PM proceeds via cytosolic Heat-shock protein/Caveolin/Chaperone/Lipid complex [37], [17].

Excess Cholesterol in the ER is esterified and the esters are stored in cytoplasmic lipid droplets [38]. Cholesteryl ester transfer protein can transport Cholesteryl ester into storage droplets [39].

Since both TGN and ERC are engaged in extensive membrane traffic, esterification of Cholesterol in these membranes may play an important role [40].

Lipid vesicle retrograde pathway from Golgi to ER is still being investigated. Cholesterol and other raft lipids are most probably not transported between the Golgi apparatus and ER this way [41].

Soluble cytosolic sterol carrier proteins transport Cholesterol to inner leaflet of PM. ATP-binding cassette family members transport mediate accumulation of Cholestero l in the outer leaflets by transporting the lipid from the inner leaflets [42], [43], [44].


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