Cholesterol and Sphingolipid transport/ Distribution to the
intracellular membrane compartments (normal and
CF pathway (highlighted in purple on map)
Cultured model CF epithelial cells exhibit intracellular accumulation of unesterified
Cholesterol in a manner similar to Niemann-Pick disease.
This leads to accumulation of free Cholesterol in late
endosomes and lysosomes , , .
Increased Cholesterol and
Sphingolipids in punctate endosomal structures indicate a
block in the translocation of Cholesterol to the ER and
Golgi from late endosomes and lysosomes . Overexpression of RAB9A member
RAS oncogene family (Rab-9) clears the punctate
Cholesterol accumulations and this might be the consequence
of Rab-9 overcoming an endosome-to-Golgi cholesterol
trafficking block in CF cells .
Cholesterol and Sphingolipids are transported from early endosomes via the
Rab-mediated mechanism. Rab-7 plays a role in the lipid
transport from early-to-late endosomes and late endosomes-to-lysosomes.
Rab-9 is thought to regulate the late
endosome-to-trans-Golgi network (TGN) transport step through
its interaction with mannose-6-phosphate receptor binding protein 1
Sphingolipids are sorted preferentially to TGN via
Rab-7 and Rab-9 interaction
. Cholesterol and, especially,
Cholesteryl ester can be sorted to both TGN and lysosome.
Rab-9 overexpression helps to clear ERC cholesterol
accumulation that by itself might be the consequence of
Rab-9 overcoming an endosome-to-Golgi
Cholesterol trafficking block in F508-expressing cells
. In lysosomes, acid cholesterol esterase
(LIPA) hydrolyses Cholesteryl
ester to free Cholesterol and fatty acids
. Sphingolipid activator proteins promote
Sphingolipids degradation by lysosomal enzymes .
Exchange of Cholestrol content between late endosomes and
lysosomes depends upon the ongoing tubulovesicular late endocytic trafficking. It is
suspected that Niemann-Pick disease type C1 protein (NPC1)
not only mediates Cholesterol efflux from the late endosome
membrane inner leaflet to the outer leaflet, but also promotes formation of tubule with
Cholesterol from lysosomes and late endosomes toward other
intracellular membranes and especially the trans-Golgi network (TGN) , , , .
Niemann-Pick disease type C2 (NPC2) protein and
NPC1 promote Cholesterol efflux
presumably via a direct interaction with the acceptor membrane. Transfer of
Cholesterol to membranes is increased in acidic environment
StAR-related lipid transfer (START) domain containing proteins 4 and 5
(StARD4 and StARD5) may capture
Cholesterol via their MENTAL domain in the late-endosomal
membranes. Cholesterol can then be transferred to the
cytosolic acceptor protein or to the membrane. START domain containing proteins has been
shown to transfer Cholesterol from other donor to acceptor
vesicles , , .
Soluble cytosolic proteins like sterol carrier protein 2
Cholesterol transfer from lysosome membrane to outer
mitochondrial membrane . 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 , , , , .
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