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 , , . 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
. Also it prevents Cholesterol biosynthesis
inhibition and promotes Cholesterol biosynthesis de novo and
ER-to-Golgi vesicle traffic , , . An
indirect marker of increased de novo Cholesterol synthesis
is increased plasma membrane Cholesterol content in CF cells
and tissues determined by electrochemical measurement , .
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
CF cells . 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 . Alterations in Cholesterol processing in CF cells
may be viewed as an adaptive mechanism for increasing the content of CFTR at the plasma
Cholesterol and Cholesteryl
ester bound to lipoprotein particles are recognized by the corresponding
receptors , , , .
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 .
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 , . 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
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
Cholesterol from internal membranes to plasmalemma,
specifically to caveolae-lipid rafts , , . As a result, ERC is one of the most
Cholesterol-rich compartments in the cell .
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) .
Sphingolipids are sorted preferentially to TGN , 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
. 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.
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)
, , , .
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
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. , , .
Soluble cytosolic proteins like sterol promote
Cholesterol transfer from the lysosome membrane to the 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 , , , , .
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 , , . Unlike Cholesterol,
Sphingomyelin is transported to the apical membrane preferentially by
De novo-synthesized Cholesterol 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 , .
Excess Cholesterol in the ER is esterified and the esters
are stored in cytoplasmic lipid droplets . Cholesteryl ester transfer
protein can transport Cholesteryl ester into storage
Since both TGN and 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.
Cholesterol and other raft lipids are most probably not
transported between the Golgi apparatus and ER this way .
Soluble cytosolic sterol carrier proteins transport Cholesterol
to inner leaflet of PM. ATP-binding cassette family members transport
mediate accumulation of Cholesterol in the outer leaflets by
transporting the lipid from the inner leaflets , , .
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