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 Cholesterol 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 Cholesterol
from inner to outer leaflets , , .
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