Physiol Rev 86: 1237–1261, 2006;
doi:10.1152/physrev.00022.2005.
Mechanisms for Cellular Cholesterol Transport:
Defects and Human Disease
ELINA IKONEN
Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland
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I. Introduction
II. Cellular Cholesterol Metabolism
A. Cholesterol biosynthesis
B. Transcriptional regulation of cholesterol homeostasis
C. Cholesterol esterification and ester hydrolysis
D. Absorption of dietary cholesterol
E. Cholesterol metabolism into bile acids, oxysterols, and steroid hormones
III. Overview of Intracellular Cholesterol Transport
A. Ports of sterol entry: endogenous synthesis and lipoprotein sterol uptake
B. Endosomal cholesterol transport
C. Cholesterol efflux
D. Intramembrane cholesterol mobility
IV. Cellular Cholesterol Transport: Lessons From Mouse Studies
A. Acyl-CoA cholesterol acyl transferases
B. Scavenger receptor-mediated cholesterol transport
C. Caveolin-1 and cholesterol transport
D. NPC1L1 and cholesterol absorption
V. Human Single Gene Disorders of Cholesterol Transport
A. Familial hypercholesterolemia: LDLR pathway
B. Wolman disease and cholesteryl ester storage disease: acid lipase deficiency
C. Niemann-Pick type C disease: egress of cholesterol from lysosomes
D. Tangier disease and familial HDL deficiency: efflux of cholesterol from cells
E. Sitosterolemia: intestinal sterol absorption
F. Smith-Lemli-Opitz syndrome and other inborn errors of cholesterol synthesis
G. Cerebrotendinous xanthomatosis and other defects of bile acid synthesis
H. Congenital lipoid adrenal hyperplasia: transport of cholesterol for steroidogenesis
I. Hypobetalipoproteinemias: defects of lipoprotein assembly
VI. Cellular Cholesterol Balance as a Target for Cardiovascular Pharmacology
VII. Cholesterol-Sphingolipid Rafts: Implications for Human Disease
VIII. Conclusions and Perspectives
Ikonen, Elina. Mechanisms for Cellular Cholesterol Transport: Defects and Human Disease. Physiol Rev 86:
1237–1261, 2006; doi:10.1152/physrev.00022.2005.—This review summarizes the mechanisms of cellular cholesterol
transport and monogenic human diseases caused by defects in intracellular cholesterol processing. In addition,
selected mouse models of disturbed cholesterol trafficking are discussed. Current pharmacological strategies to
prevent atherosclerosis are largely based on altering cellular cholesterol balance and are introduced in this context.
Finally, because of the organizing potential of cholesterol in membranes, disturbances in cellular cholesterol
transport have implications for a wide variety of human diseases, of which selected examples are given.
I. INTRODUCTION
During the past 15 years, an increasing number of
gene defects have been identified that underlie cellular
cholesterol transport defects in humans. Familial hypercholesterolemia is the prototype of this group of diseases,
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and the major advances in understanding its pathogenesis
and treating the disease have served as a model for studying other disorders. Often, these diseases have helped to
pinpoint critical steps of cholesterol trafficking, and the
characterization of the defective proteins has provided
insights into the molecular machineries operating at these
0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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ELINA IKONEN
II. CELLULAR CHOLESTEROL METABOLISM
A. Cholesterol Biosynthesis
The 27-carbon tetracyclic cholesterol molecule is
synthesized from acetate in a series of ⬃30 enzymatic
reactions. The rate-limiting enzyme of the pathway is
hydroxymethylglutaryl CoA reductase (HMG-CoAR),
which generates mevalonate. This enzyme harbors a conserved sterol-sensing domain (SSD) with five membranespanning ␣-helices that is shared by other proteins implicated in sterol regulation (186). The SSD of HMG-CoAR is
critical for the association of the protein with the endoplasmic reticulum (ER) resident protein Insig and regulation of its degradation (208). Production of the first sterol
in the cascade, lanosterol, is catalyzed by squalene cyclase. The subsequent ⬃20 steps constitute the postlanosterol part of cholesterol biosynthesis in which douPhysiol Rev • VOL
ble bonds are reduced, their positions altered, and methyl
groups removed. Importantly, isoprenoid intermediates in
the presqualene half of the pathway serve as precursors
not only for cholesterol but also for a number of other
biomolecules involved in transcription (isopentenyl
tRNAs), protein N-glycosylation (dolichol), protein prenylation (farnesyl and geranylgeranyl moieties), and mitochondrial electron transport (ubiquinone).
The ER is the primary site of cholesterol synthesis
(189) (see Fig. 1). The first seven enzymes of cholesterol
biosynthesis are soluble proteins apart from HMG-CoAR,
which is an integral ER membrane protein. HMG-CoAR
and some of the other prelanosterol biosynthesis enzymes
are also present in peroxisomes (118), but the enzyme
directly following HMG-CoAR, mevalonate kinase, is cytosolic (94). The post-lanosterol enzymes are localized to
the ER or its extensions, nuclear envelope, or lipid droplets. The significance of this complex subcompartmentalization of the cholesterol biosynthetic pathway remains
poorly understood.
B. Transcriptional Regulation
of Cholesterol Homeostasis
Due to the low ER cholesterol level, its cholesterol
concentration fluctuates much more than that of the
plasma membrane upon cholesterol loading (233). The ER
sterol levels are sensed by the main cellular cholesterol
homeostatic machinery, constituted of membrane-embedded ER proteins (78). In short, the mature SREBP transcription factor is generated in the Golgi complex and
translocates to the nucleus to activate genes involved in
cholesterol synthesis and uptake. In the presence of ample cholesterol, SREBP transcriptional activity is suppressed by ER retention (Fig. 2). This is mediated by
interaction with the SSD protein SCAP, which in turn
binds the ER retention protein Insig. Insig also binds the
SSD protein HMG-CoAR in a sterol-dependent manner.
This binding enhances degradation of the reductase.
Another transcriptional regulatory network is orchestrated by the nuclear hormone receptors liver X receptor (LXR) and peroxisome proliferator activated
receptor (PPAR) (Fig. 2). These constitutively nuclear
receptors are activated by oxysterols and fatty acids,
respectively, and regulate the expression of several key
proteins of the cholesterol and fatty acid metabolic pathways (15).
C. Cholesterol Esterification and Ester Hydrolysis
The 3⬘-OH group of cholesterol can become fattyacylated to form cholesterol esters that can be stored in
cytoplasmic lipid droplets (Fig. 1). The enzyme responsible for this activity is acyl-CoA:cholesterol acyltrans-
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steps. In the first part of this review, the key processes of
cellular cholesterol metabolism are summarized (sect. II)
and general principles of cellular cholesterol transport
are introduced (sect. III). Until now, the progress in understanding intracellular cholesterol movement has
largely relied on the characterization of relatively rare
single gene diseases, and the description of such disorders constitutes the body of this review (sect. V). In addition, selected other proteins that play key roles in cellular
cholesterol movement based on mouse models are discussed (sect. IV). Pharmacological strategies currently
used to treat cardiovascular diseases are briefly mentioned because many of them rely on effects on cellular
cholesterol trafficking (sect. VI). Finally, because of the
organizing potential of cholesterol in the membrane, cellular cholesterol transport processes and their disturbances have implications for a wide variety of human
diseases. Selected examples are given in section VII.
The topic of this review, intracellular cholesterol
transport, spans into several medical specialties including
internal medicine, pediatrics, neurology, and surgery and
integrates information from basic sciences such as organic chemistry and biophysics. Comprehensive coverage
of the research addressing intracellular cholesterol transport and human disease is not possible within the limits of
this review. Typically, correlative evidence for the association of specific genetic variations or protein expression
levels with metabolic changes has not been included if a
liable causal relationship to cellular cholesterol transport
is lacking. I have also aimed to underscore medically
relevant aspects of the conditions at the expense of technical subtleties. Importantly, a number of excellent reviews have recently been written on highly popular areas
of study, and the reader is referred to these articles for
more in-depth information.
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
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ferase (ACAT) (also termed sterol O-acyltransferase,
SOAT), an integral protein of the ER (32). There are two
homologs of mammalian cholesterol esterifying enzymes,
ACAT1 and ACAT2, that are differentially expressed.
ACAT1 is expressed in many tissues and cell types, with
the highest levels in macrophages and in the adrenal and
sebaceous glands. ACAT2, on the other hand, is more
restricted in tissue distribution, being the dominant ester-
FIG. 2. Schematic illustration of the
transcriptional regulation of cholesterol
homeostasis. The sterol-sensing domain
(SSD) proteins SCAP and HMG CoAR
bind to the ER retention protein Insig in
the presence of high cholesterol or lanosterol levels, respectively. Insig binding
prevents the transport of SCAP-SREBP
complex in COPII-coated vesicles to the
Golgi complex where the active SREBP
transcription factor is released. Consequently, the transcription of sterol response element-regulated genes is not
turned on. Binding of HMG CoAR to Insig
leads to its retro-translocation and proteasomal degradation. Conversely, cholesterol depletion promotes the rapid
proteasomal degradation of Insig, which
is prevented by cholesterol restoration.
Oxysterols and fatty acids act in the nucleus to activate LXR and PPAR-dependent gene transcription, respectively. Selected target genes of the transcriptional
regulators are indicated.
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FIG. 1. Cellular cholesterol distribution and key enzymes of cellular cholesterol metabolism. The approximate cholesterol content of the membrane is
indicated by shades of gray. The main
processes of cholesterol metabolism, key
enzymes involved, and their subcellular
locations are indicated (see text for
details).
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ELINA IKONEN
liver, nCEH activity appears to respond to changes in
cholesterol flux through the liver (76). The breakdown of
cholesterol esters that enter the cell by uptake of LDL
particles is catalyzed by acid lipase in the endosomal
compartment (see below).
D. Absorption of Dietary Cholesterol
Dietary cholesterol is absorbed from bile salt micelles with fatty acids and lysophospholipids in the proximal parts of the small intestine. Key proteins involved in
dietary cholesterol uptake by the enterocytes have been
identified during the past few years. It has become evident
that a protein belonging to the SSD proteins, NPC1L1,
plays an important role in this process (6). The NPC1L1
protein is localized to the brush-border membrane of
enterocytes and is required for intestinal uptake of both
cholesterol and plant sterols (phytosterols) (49) (Fig. 3).
Recent evidence suggests that this protein is the target of
the cholesterol-lowering drug ezetimibe (72, 272).
Whether NPC1L1 functions as a genuine cholesterol
transporter promoting cholesterol transfer through the
plasma membrane or is indirectly involved in the process
is not yet known. In addition, the ABC transporter family
half-transporters ABCG5 and ABCG8 (sterolin-1 and sterolin-2) constitute a functional heterodimeric unit limiting
sterol absorption (81, 245) (Fig. 3). The role of ABCG5
and ABCG8 in dietary cholesterol absorption may not be
direct, i.e., inhibition of dietary cholesterol uptake by
enterocytes; rather, this transporter stimulates hepatic
sterol excretion into the bile (see sect. IIE), and thereby
modulates the bile-acid/sterol ratio, possibly to promote
the secretion of absorbed sterols from the intestinal epithelium back into the gut lumen (101).
FIG. 3. Key proteins involved in cholesterol trafficking in lipoprotein-secreting cells. Three main lipoproteinsecreting cell types of the body are schematically illustrated, and key proteins implicated in the process are
indicated. For the enterocyte and hepatocyte proteins
shown, mutations causing cholesterol transport diseases
have been characterized (see text for details). Intestinal
and hepatic lipoproteins are further processed in the circulation before cellular uptake. Less information is available for astrocyte lipoprotein secretion, but recent evidence points to the importance of ApoE and select ABC
transporters (3, 110).
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ifying enzyme in the mouse liver and small intestine (26).
Also in adult humans, ACAT2 is localized to hepatocytes
and enterocytes (180).
ACAT activity is allosterically activated by high cholesterol levels (32). A conserved His residue located
within a long stretch of hydrophobic amino acids may
serve as an active site for ACAT catalysis (129). ACAT1
produces cholesterol esters to be stored in lipid droplets
in macrophages while ACAT2 serves to esterify cholesterol to be included in apolipoprotein B (apoB)-containing lipoproteins, such as chylomicrons in enterocytes and
possibly very-low-density lipoprotein (VLDL) in hepatocytes. However, the functional cooperation of ACAT1 and
ACAT2 in the assembly of apoB-containing lipoproteins
remains to be established (33). The intracellular localization of the ACAT enzymes has been reported only for
ACAT1. In macrophages and fibroblasts, ACAT1 is mostly
localized in the ER (197). In addition, macrophage ACAT1
has been found in a region close to the trans-Golgi network and endocytic recycling compartment (113).
Cellular cholesterol undergoes a continuous cycle of
esterification and ester hydrolysis even under conditions
in which no external cues altering cholesterol balance are
introduced. Net breakdown of cholesterol esters in lipid
droplets takes place when cellular cholesterol levels fall.
The enzyme responsible for the degradation of cholesterol esters in lipid droplets is neutral cholesterol ester
hydrolase (nCEH) (Fig. 1). There are a number of nCEH
enzymes that differ between cell types. Hormone-sensitive lipase (HSL) is responsible for cholesterol ester
breakdown in steroidogenic cells (269), whereas other
nCEHs have been cloned from monocyte/macrophages
and hepatic cells (74, 75). The mechanisms by which this
enzyme activity is regulated is not well understood. In the
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
E. Cholesterol Metabolism Into Bile Acids,
Oxysterols, and Steroid Hormones
1. Bile acid synthesis
2. Hydroxylated sterol derivatives
Cholesterol or its sterol precursors serve as starting
material for the production of oxysterols and vitamin D.
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Oxysterols function as signaling molecules by serving as
ligands for LXR transcription factors (15). Furthermore,
oxysterols represent a mechanism for export of cholesterol in a more hydrophilic form from other tissues to the
liver (169). The most abundant oxysterol in plasma is
27-hydroxycholesterol, which is produced by the mitochondrial sterol 27-hydroxylase (Cyp27a, Fig. 1). 25-Hydroxylase (which in contrast to many of the other enzymes involved in bile acid or oxysterol production is a
non-P-450 cytochrome) is localized primarily in the ER
(135). Both 25- and 27-hydroxycholesterol are partial LXR
agonists, whereas 24(S),25-epoxycholesterol is a strong
agonist. 24(S),25-Epoxycholesterol is produced by diversion from the cholesterol biosynthetic pathway (224).
Vitamin D is also produced by hydroxylation of a cholesterol biosynthetic precursor, 7-dehydrocholesterol, to
produce previtamin D3. D3 is further hydroxylated in the
kidney and liver to produce active vitamin D (1,25-dihydroxyvitamin D) (95).
3. Steroid hormone synthesis
Cholesterol serves as an obligatory precursor for
steroid hormone production in steroidogenic tissues,
such as the adrenals, gonads, placenta, and brain. Regardless of the tissue of origin or the steroid hormone to be
produced, steroidogenesis is initiated by the cleavage of
the cholesterol side chain to produce pregnenolone. The
protein catalyzing this reaction, P-450 side chain cleavage
(P450scc/CYP11A1) enzyme, is located in the inner mitochondrial membrane (154) (Fig. 1). This enzyme activity is
not rate limiting in the process; instead, it is the delivery
of cholesterol to the enzyme by steroidogenic acute regulatory protein (StAR), a cytosolic protein with a mitochondrial targeting signal. The precise site of action of
StAR is controversial, but recent data provide strong evidence for a function in the outer mitochondrial membrane (21). According to the “cholesterol desorption
model” (229), StAR interacts with the mitochondrial outer
membrane where it stimulates cholesterol desorption,
perhaps through preexisting contact sites between the
outer and inner mitochondrial membrane. The import of
StAR into mitochondria would therefore remove the protein from its site of action and terminate sterol entry into
mitochondria. A candidate protein for the transport of
cholesterol from the outer to the inner membrane is peripheral-type benzodiazepine receptor (PBR) that is localized in the outer membrane at contact sites with the inner
membrane (173).
Steroids made locally in the brain are called neurosteroids. They are multifunctional lipids that mediate
their actions, not through classic steroid hormone nuclear
receptors, but through ion-gated neurotransmitter receptors (43). In addition to modulation of receptor activity,
the functions attributed to specific neurosteroids include
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Cholesterol cannot be degraded by cells into noncyclic hydrocarbon products. However, hepatocytes can excrete it into the bile to be removed in feces. For this,
cholesterol to be removed from extrahepatic tissues
needs first to be transported via the circulation to the
liver. The process involving cholesterol efflux from extrahepatic tissues and return to the liver for secretion into
bile and disposal via the feces is called reverse cholesterol
transport (64). Within hepatocytes, cholesterol secretion
necessitates its conversion to bile salts. In humans, this
conversion accounts for roughly half of the daily elimination of cholesterol from the body. The majority of the rest
is secreted into bile as free cholesterol (117). Remarkably,
recent evidence suggests that a considerable fraction of
cholesterol disposed in the feces may be excreted directly
via the intestine, constituting a more direct route for
cholesterol removal (120).
Cholesterol can be converted into bile salts via two
pathways: the classic or neutral pathway and the alternative or acidic pathway (117). The key regulatory enzyme
in the classic pathway is cholesterol 7␣-hydroxylase
(CYP7A1) and in the alternative pathway sterol 27-hydroxylase (CYP27A). CYP7A1 resides in the ER (19) and
CYP27A in mitochondria (168) (Fig. 1). The neutral,
CYP7A1 pathway is liver specific. Instead, CYP27A activity is present in almost all tissues, and in extrahepatic
tissues its expression is probably related to the production of oxysterols. Oxysterol 7␣-hydroxylase (CYP7B1)
catalyzes the second step, i.e., conversion of 27-hydroxycholesterol (as well as that of 24 and 25-hydroxycholesterol) to 7␣-hydroxylated oxysterols, and is also involved
in the regulation of the rate of cholesterol secretion into
bile. Yet another important parameter regulating the biliary cholesterol secretion rate is the hydrophobicity of the
bile salt. This is governed by the enzyme sterol 12␣hydroxylase (CYP8B1) that controls the ratio of cholic
acid and chenodeoxycholic acid synthesis in both the
neutral and acidic pathways.
The molecular mechanisms by which cholesterol is
secreted into bile have recently been unraveled. The heterodimeric ABC transporter ABCG5/G8 mediates biliary
cholesterol secretion at the apical membrane of hepatocytes (82, 274). Importantly, increased G5/G8 expression
results in elevated biliary cholesterol secretion, suggesting that the transporter levels, rather than cholesterol
delivery to it or biliary acceptors, are rate limiting (273).
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ELINA IKONEN
regulation of myelinization, neuroprotection, and growth
of axons and dendrites.
III. OVERVIEW OF INTRACELLULAR
CHOLESTEROL TRANSPORT
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A. Ports of Sterol Entry: Endogenous Synthesis
and Lipoprotein Sterol Uptake
Essentially all nucleated cells synthesize cholesterol.
Newly synthesized cholesterol leaves the ER rapidly and
moves against a steep concentration gradient to reach the
plasma membrane (Fig. 4). Secretory transport via the
Golgi apparatus plays a minor role in this process (92,
247), while the bulk of sterol can reach the plasma membrane by nonvesicular mechanisms (14). Notably, sterol
precursors also traffic between the ER and plasma membrane (123) and can be effluxed to extracellular acceptors
(137). Indeed, serum sterol precursor (typically lathoste-
FIG. 4. Key proteins governing cellular cholesterol distribution and
flow. Major (continuous lines) and minor (discontinuous lines) routes of
cholesterol trafficking are indicated by arrows. Endogenously synthesized cholesterol as well as cholesterol precursors reach the plasma
membrane mostly via Golgi bypass route(s). Lipoprotein cholesterol is
internalized via receptor-mediated uptake and reaches the endocytic
circuits from where it is redistributed to the plasma membrane, Golgi
complex, and ER. ARH, functioning in the endocytic routing of LDL
receptors, and several Rab proteins regulating membrane trafficking are
involved in endosomal cholesterol movement. Some of the cholesterol
interacting proteins, such as NPC1, NPC2, and MLN64, localize mostly to
late endocytic compartments while caveolin localizes to plasma membrane caveolae and lipid droplets, as well as the Golgi complex and
caveosomes. Several ABC transporters synergize to mediate cholesterol
efflux.
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As described above and illustrated in Figure 1, cholesterol metabolism is compartmentalized into distinct
subcellular membranes. Moreover, the cholesterol concentration of cellular membranes is highly variable. The
majority of cellular cholesterol resides in the plasma
membrane. In addition, endocytic and exocytic membrane trafficking routes connecting the endosomes and
the trans-Golgi network to the plasma membrane have
cholesterol-enriched domains (216). In contrast, the ER
and mitochondria where many critical enzymatic reactions of cholesterol metabolism take place are relatively
cholesterol poor (Fig. 1). Thus maintenance of cellular
cholesterol homeostasis necessitates the transport of
cholesterol between subcellular membranes and its exchange with lipoproteins.
Our understanding of cellular cholesterol trafficking
is lagging behind the knowledge on protein trafficking.
This is largely due to technical limitations in the available
methodologies. Monitoring a metabolic conversion or an
enzymatic reaction provides an indirect means of tracing
cellular cholesterol. In addition, cholesterol movement
can be measured by radiolabeling cholesterol or its precursor molecules and following partitioning of the lipid
between biochemically resolved subcellular compartments. The cellular distribution of sterols with a free
3⬘-OH group can be directly visualized in cells by using the
cholesterol-binding and membrane-permeabilizing agent
filipin. The development of more sophisticated cell biological strategies, e.g., direct visualization of the itineraries of fluorescent sterol derivatives, is providing increasing insight into sterol movement by enabling live cell
monitoring.
Due to its hydrophobicity, spontaneous exchange of
cholesterol from one membrane to another across the
aqueous cytoplasm is slow. In living cells, this movement
takes place by a combination of vesicular trafficking and
nonvesicular mechanisms (148), such as cytosolic carrier
proteins (StAR being the best characterized example; Ref.
154), and most likely via protein-mediated membrane contact sites (170). Assessment of the quantitative contribution of each mechanism is hampered by the possible use
of bypass mechanisms upon blocking one route or protein. Membrane trafficking encompasses the selection of
cargo into forming vesicles, and cholesterol carrier proteins are known to have targeting information for specific
membranes. Yet, especially under conditions where cells
are challenged with massive fluxes of cholesterol, such
mechanisms seem inefficient (carrier proteins) or may be
preoccupied by other cargo (vesicular trafficking). Feasible mechanisms to handle such conditions may be diffusion via membrane contact sites or specialized vesicles. In
the following, a brief summary of intracellular cholesterol
trafficking pathways is provided. For more in-depth information, the reader is referred to excellent recent reviews
(147, 221).
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
B. Endosomal Cholesterol Transport
Endocytic circuits harbor substantial amounts of
cholesterol that they acquire not only from lipoprotein
uptake but apparently also via membrane recycling and
nonvesicular equilibration. Endosomal cholesterol may
return to the plasma membrane directly or via the Golgi
complex, or be transported to the ER (Fig. 4) where it
regulates cholesterol homeostasis (Fig. 2). The mechanisms and routes of cholesterol exit from the endocytic
circuits remain rather poorly defined. Two proteins, NPC1
and NPC2, are implicated in the process because of disease-causing mutations (34). Moreover, the late endosomal membrane system seems to maintain a delicate cholesterol balance that can be deranged by various cues,
such as disturbing the functional cycle of Rab GTPases
(98), deleting lysosomal membrane proteins (59), or disturbing the lipid assembly of intraendosomal membranes
(116). Hence, some cholesterol-binding proteins such as
MLN64 may safeguard the local cholesterol content in
functionally important endosomal membrane domains
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(96). Endosomal cholesterol transport is more comprehensively discussed in several recent reviews (34,
97, 230).
C. Cholesterol Efflux
The atheroprotective function of high-density lipoprotein (HDL) is thought to be mediated by its ability to
transport excess cholesterol from peripheral tissues to
the liver for excretion in a process known as reserve
cholesterol transport. In this process, cholesterol is released from peripheral cells to poorly lipidated apolipoproteins, in particular apolipoprotein A-I (apoA-I)
which, upon further lipidation, is converted to mature
HDL particles. The ATP-binding cassette transporter
ABCA1 controls the rate-limiting step in HDL assembly by
mediating cholesterol and phospholipid efflux from cells
to apoA-I, generating nascent pre-␤-HDL (270). These particles may serve as substrates for ABCG1-mediated removal of cholesterol to more mature HDL subclasses
(HDL2, HDL3) (73, 257) (Fig. 4). HDL is remodeled in the
plasma, and additional cellular cholesterol may be transferred to the growing particle by scavenger receptor class
B type 1 (SR-B1) (276). SR-B1 can also mediate the last
step of reverse cholesterol transport, namely, delivery of
cholesteryl esters from HDL to the liver without HDL
degradation, termed selective cholesteryl ester uptake
(119).
The relative contribution of cell surface versus intracellular events in cholesterol efflux and the interplay of
the individual receptors in key tissues such as the liver,
steroidogenic tissues, and macrophages warrant further
investigation. Apparently, ABCA1-mediated lipid efflux to
apoA-I takes place from the cell surface, but endocytic
circuits play an important role (164). The surface appearance of ABCA1 is in part regulated by endocytic trafficking of the transporter (see sect. IVD). The term retroendocytosis was introduced to describe the internalization
of HDL into the cell and subsequent release after lipidation (203), but the concept remains controversial. Recent
evidence suggests that SR-B1 can mediate holo-HDL particle uptake followed by HDL resecretion and that this
may facilitate cholesterol efflux (172). Whether selective
cholesteryl ester uptake also involves holoparticle endocytosis or takes place only at the cell surface remains
disputed (see, e.g., Refs. 89, 212).
D. Intramembrane Cholesterol Mobility
Considering that the exchange of cellular and exogenous cholesterol pools with acceptor/donor lipoproteins
takes place in the exoplasmic leaflet of the membrane, a
critical parameter regulating this process is the transbilayer movement of cholesterol. Kinetic estimates have
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rol) levels are used to estimate the level of body cholesterol synthesis.
On a Western diet, humans synthesize an estimated
⬃1 g of cholesterol/day and ingest ⬃400 mg (85). For
intercellular exchange via the interstitial fluid and blood,
both pools are incorporated into lipoprotein particles.
The major lipoprotein-secreting cells of the body and their
sterol sources are summarized in Figure 3.
The majority of cholesterol entering the cells is taken
up by receptor-mediated uptake from lipoproteins. The
core of lipoprotein particles is composed of triglycerides
and cholesterol esters (i.e., fatty acylated cholesterol),
while the particle surface is covered by phospholipids and
free cholesterol. Low-density lipoproteins (LDL) are internalized via clathrin-coated pits into early endosomes from
where the receptor is recycled to the cell surface (145)
and the LDL-particle targeted for proteolytic and lipolytic
degradation. The enzyme responsible for the hydrolysis of
cholesterol esters, lysosomal acid lipase, was recently
shown to be present not only in lysosomes as traditionally
thought but also in earlier endocytic compartments (231).
This suggests that the particle breakdown is initiated
rapidly after internalization.
Dietary lipoproteins are packaged into chylomicrons
from which fatty acids are lipolyzed to produce cholesteryl ester-enriched lipoprotein remnant particles.
They are rapidly removed from the circulation primarily
by the liver in a system involving the LDL receptor (LDLR)
and LDLR-related protein (LRP) (102, 271). The latter
differs mechanistically from LDLR uptake and is dependent on hepatic secretion of apoE to enrich the remnants
with a ligand for receptor-mediated endocytosis (130).
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IV. CELLULAR CHOLESTEROL TRANSPORT:
LESSONS FROM MOUSE STUDIES
Some of the proteins introduced in previous sections
are implicated in cellular cholesterol transport, but no
human diseases resulting directly from their mutations
have been reported. In this section, selected proteins from
this category are discussed. The pathophysiological relevance of these proteins is supported by evidence from
mouse models. The most popular mouse models for
studying atherosclerosis are the LDLR- and apoE-defiPhysiol Rev • VOL
cient mice. Notably, there are significant differences, both
quantitatively and qualitatively, in the cholesterol balance
between mouse and human (51). In particular, the high
rate of hepatic LDL clearance leads to a low steady-state
concentration of cholesterol carried in LDL, and consequently, a less dramatic phenotype when the LDLR is
nonfunctional in mice compared with humans. ApoE is a
glycoprotein constituent in all lipoproteins except LDL
and a principal protein component of chylomicron remnants, very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), functioning as a ligand for
receptors that clear chylomicrons and VLDL remnants
(151). ApoE-deficient mice, generated in 1992 by two
groups (177, 178), are perhaps the most popular murine
model for studying atherosclerosis because of its propensity to spontaneously develop atherosclerotic lesions on a
standard diet. Foam cell lesions can be observed already
at 10 wk of age and fibrous plaques at 20 wk. A Westerntype diet accelerates the process. However, despite inbreeding, the mouse-to-mouse variability remains high
(151).
A. Acyl-CoA Cholesterol Acyl Transferases
The deposition of cholesteryl esters in macrophages
and smooth muscle cells in the arterial intima is the
hallmark of atherosclerosis. Because ACAT is the enzyme
catalyzing intracellular cholesterol esterification, its inhibition should reduce atherogenesis. Knock-outs of both
ACAT1 and ACAT2 genes have been generated in the
mouse and found to produce differential phenotypes, reflecting distinct tissue distributions and biochemical characteristics of the enzymes.
In ACAT1-deficient mice, lack of the enzyme is manifested in macrophages and adrenal cortex, but plasma
cholesterol levels, hepatic cholesterol esterification, and
intestinal cholesterol absorption are normal (150).
ACAT1-deficient mice have been crossed with LDLR- and
ApoE-deficient mice. However, atherosclerosis was not
significantly inhibited in either model. In fact, when
LDLR-deficient mice were substituted with macrophages
from ACAT1⫺/⫺ mice, the development of atherosclerotic lesions was accelerated (62). This was attributed, at
least in part, to the increased apoptosis of macrophages
due to the toxic effects of increased free cholesterol
levels. Instead, ACAT2-deficient mice lack cholesteryl esters in the liver and small intestine (26). They were protected from diet-induced hypercholesterolemia and cholesterol gallstones because of the reduced capacity to
obtain cholesterol from the diet. Interestingly, ApoE⫺/⫺
ACAT2⫺/⫺ mice atherosclerotic lesion development was
almost completely inhibited (265). The toxic effects of
ACAT inhibition may be less severe with partial, pharmacological inhibition of the enzyme. Currently, ACAT inhi-
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been highly variable, but the available evidence points to
a rapid spontaneous flipping of cholesterol between the
two bilayer leaflets (225). However, this may not necessarily indicate an equal transbilayer distribution of cholesterol as energy-dependent flippases and the higher affinity of cholesterol for distinct lipid environment(s) probably contributes. At present, the transbilayer distribution
of cholesterol is not known.
In model membranes, cholesterol exhibits high affinity towards sphingolipids. This is considered to derive
from the favorable packing of the rigid sterol ring structure between the long and saturated acyl chains and
sphingosine backbone of sphingolipids (217). The attractive forces involved are weak intermolecular interactions
such as van der Waals interactions within the bilayer and
hydrogen bonding between lipid head groups and in the
water-lipid interphase. The predicted preferential association of cholesterol with sphingolipids forms the basis of
the lipid raft concept (215). According to this hypothesis,
these lipid interactions described in model systems may
also apply in living cells to favor the formation of membrane domains that function in diverse cellular processes.
Such lipid assemblies may contribute for instance to signal transduction, membrane transport, intramembrane
proteolysis, cell adhesion, and invasion of pathogens. A
morphologically identifiable subtype of lipid rafts are
caveolae, plasma membrane invaginations formed upon
polymerization of the structural protein caveolin in a
cholesterol-dependent manner (174).
Obviously, the molecular interaction networks operating in living cells are complex, involving not only interlipid interactions but also lipid-protein and protein-protein interactions. Moreover, the strict requirement of a
particular lipid species appears not to apply because in
the absence of such species most cells can probably
compensate by generating analogous biophysical membrane characteristics using other lipid combinations. In
spite of, or perhaps because of, its hypothetical nature,
the lipid raft concept has generated much interest and
resulted in a steadily increasing account of reports that
implicate rafts as regulators of biological or pathological
processes.
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
bition is a promising avenue of intervention with atherosclerosis development, and clinical trials in patients are
underway (133).
B. Scavenger Receptor-Mediated
Cholesterol Transport
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The class E scavenger receptor lectin-like oxidized
LDLR (LOX-1) is the major receptor for oxidized LDL in
endothelial cells (201) and is also expressed in macrophages and smooth muscle cells (36). Its expression is
increased in the endothelium of early atherosclerotic lesions (35), most prominently in arterial bifurcations (37)
that are considered as atherosclerosis susceptible sites.
Importantly, downregulation of LOX-1 was shown to prevent monocyte adhesion to endothelial cells and apoptosis (126). Moreover, genetic evidence points to the involvement of LOX-1 in human atherosclerotic conditions;
a polymorphism was reported to be associated with myocardial infarction (237) and inversely associated with the
severity if coronary artery disease (167). Further functional and epidemiological studies are clearly warranted.
C. Caveolin-1 and Cholesterol Transport
Caveolae are a subset of plasma membrane cholesterol-sphingolipid rafts (134, 215), and caveolin-1, the
structural protein of caveolae, is one of the first and most
abundant molecularly identified cellular cholesterol-binding proteins (161, 194, 238). The numerous roles assigned
for the caveolin family of proteins (caveolin-1, -2, and -3)
in human pathological conditions have recently been
comprehensively reviewed in this series (40). Therefore,
the present discussion is limited to the most direct and
pathophysiologically relevant connections between
caveolins and cholesterol transport.
A number of cell culture studies have provided partially contradictory evidence for the role of caveolin-1 in
cellular cholesterol trafficking, either as a chaperone
complex via the cytoplasm or by regulating cholesterol
influx or efflux via plasma membrane caveolae (103). Yet,
no abnormalities in plasma cholesterol levels were observed in caveolin-1 null mice (188), and they also showed
normal cholesterol absorption (251). However, a caveolin-1/apoE double knock-out mouse was protected from
the development of atherosclerosis, despite hypercholesterolemia (66), suggesting that the involvement of caveolin in cholesterol trafficking may become manifested
upon a stress situation.
Interestingly, the caveolin-1-deficient mice (that also
have low levels of caveolin-2 because of degradation of
the protein in the absence of caveolin-1) show reduced
adiposity and are protected from diet-induced obesity
(188). This phenotype resembles the one found in mice
deficient in perilipin, a protein involved in adipocyte lipolysis (236). Indeed, caveolin-1 null mice appear to have
a blunted response to lipolytic agonists (40). There is
mounting evidence for a link between caveolin-1, perilipin, and protein kinase A in the regulation of lipid droplet
turnover (40, 144), but the precise connections remain to
be established. Nevertheless, adipocyte lipid droplets
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Scavenger receptors bind chemically modified lipoproteins, in addition to a number of other ligands.
Uptake of modified LDL is considered to be an early event
in vascular disease, and scavenger receptor function is
critical in this context. Class A scavenger receptor (SR-A)
was the first receptor shown to bind acetylated LDL (50,
79). Oxidatively modified LDL (oxLDL) is scavenged by
both SR-A and the SR-B protein CD36. SR-A and CD36
have been implicated as proatherogenic proteins (121),
and CD36 knock-out mice display smaller atherosclerotic
lesions (63).
On the other hand, scavenger receptor class B type 1
(SR-B1) is the first characterized cell surface receptor for
HDL, with an established antiatherogenic activity (243).
SR-B1 is expressed in various tissues, with high levels,
e.g., in the liver and steroidogenic cells. SR-B1 mediates
the selective uptake of cholesteryl esters from HDL in a
process that does not involve net internalization and degradation of the lipoprotein (119). Importantly, SR-B1 appears to be the only molecule responsible for hepatic
selective cholesteryl ester uptake from HDL (25, 171). In
addition, SR-B1 stimulates bidirectional flux of free cholesterol between cells and HDL (86, 268), and its expression levels correlate with cholesterol efflux to HDL (106).
However, the relevance of SR-B1-mediated cholesterol
efflux for HDL metabolism in vivo has not been established.
The importance of SR-B1 in HDL metabolism and its
antiatherogenic activity has been elucidated by SR-B1
gene manipulation in mice. SR-B1 deficiency results in the
accumulation of large HDL particles in the plasma and
increased circulating cholesterol levels (191). Importantly, double knock-out mice lacking both apoE and
SR-B1 develop occlusive coronary arterial lesions, multiple myocardial infarctions, and heart failure and die prematurely (23). SR-B1 is also implicated in the clearance of
apoB-containing lipoproteins, including LDL and VLDL
(242, 255). In macrophages, SR-B1 may induce foam cell
formation by binding atherogenic lipoproteins while cellular cholesterol efflux to HDL via SR-B1 would serve to
prevent foam cell formation (58). The atheroprotective
effect of SR-B1 in macrophages appears to depend on the
time of transplantation and follow-up (253). Of note, while
the atheroprotective function of SR-B1 at the level of the
organism is well established in mice, the role of the
human SR-B1 homolog CLA-1 in coronary artery disease
remains largely unknown.
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contain high levels of free cholesterol (up to 30% of total
cellular cholesterol), and this cholesterol can be readily
mobilized (181), suggesting that lipid droplets represent
an important station of cholesterol trafficking in these
cells.
Table 1. The emphasis is in the molecular basis of the
diseases, but brief descriptions of the prevalence, clinical
manifestations, diagnostic principles, and/or therapeutic
strategies when applicable are included.
A. Familial Hypercholesterolemia: LDLR Pathway
D. NPC1L1 and Cholesterol Absorption
V. HUMAN SINGLE GENE DISORDERS
OF CHOLESTEROL TRANSPORT
In this section, human diseases assigned to defects of
cellular cholesterol transport are discussed. The disorders and the genes mutated therein are summarized in
TABLE
1.
Single gene disorders of cholesterol transport
Disease
Mutant Protein(s)
Familial hypercholesterolemias
Autosomal dominant
Autosomal recessive
Wolman disease, cholesteryl ester storage disease
Niemann-Pick type C disease
Tangier disease
Sitosterolemia
Smith-Lemli-Opitz syndrome
Cerebrotendinous xanthomatosis
Congenital lipoid adrenal hyperplasia
Hypobetalipoproteinemias
Abetalipoproteinemia
Chylomicron retention disease, Anderson disease
Familial hypobetalipoproteinemia
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LDLR, apoB, PCSK9
ARH
LAL
NPC1, NPC2
ABCA1
ABCG5, ABCG8
7-Dehydrocholesterol reductase
CYP27A
StAR
MTP
Sar1b
ApoB
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The critical role of NPC1L1 in dietary cholesterol
absorption was revealed by generation of mice lacking the
protein. The NPC1L1-deficient mice showed a substantial
reduction in intestinal cholesterol and sitosterol absorption (6) and were resistant to diet-induced cholesterol
accumulation (48). This phenotype is reminiscent of that
produced by the cholesterol absorption inhibitor
ezetimibe. Moreover, the drug binds specifically to
NPC1L1 (72), strengthening the idea of NPC1L1 involvement in cholesterol absorption and showing that NPC1L1
is a target of the drug. Interestingly, NPC1L1 contains a
SSD (47), and recent data suggest that, similarly to some
other SSD-containing proteins, its intracellular trafficking
is regulated by cholesterol. The predominantly intracellular protein translocated to the cell surface in cholesterolpoor conditions, and this shift was accompanied by increased, ezetimibe-sensitive cholesterol uptake (272). Notably, genetic variation in NPC1L1 was recently
associated with reduced cholesterol absorption in a population study (42), reinforcing the medical relevance of
this protein.
Familial hypercholesterolemia (FH) is one of the
most common inborn errors of metabolism and the most
common in the category of monogenic defects of cellular
cholesterol processing (80). In most cases, it is an autosomal dominant disorder, with the heterozygous state
affecting ⬃1 in 500 individuals (estimated 10 million
worldwide). There is a strong gene dosage effect, and the
rare homozygous FH patients exhibit a very severe clinical phenotype. The majority are caused by mutations in
the LDLR gene. A rarer, clinically indistinguishable phenotype is caused by mutations in apoB, the ligand for the
LDLR. In the latter case, the disease is referred to as
familial defective apoB-100.
A third locus underlying autosomal dominant hypercholesterolemia, PCSK9 (proprotein convertase subtilisin
kexin 9), was recently identified (2). In addition to an
increasing number of patient mutations, there is suggestive evidence for the involvement of PCSK9 gene variants
in affecting total and LDL cholesterol levels in the population (210). PCSK9 is a serine protease in the secretory
pathway (206) and plays an important role in controlling
LDLR levels, but the precise mechanism remains to be
resolved. In principle, increased LDL cholesterol in the
absence of PCSK9 function could reflect decreased clearance or increased hepatic secretion of apoB-containing
lipoproteins. Both possibilities are being investigated
(149).
Due to the FH mutations, LDL is not efficiently
cleared from the circulation, and the resultant high LDL
levels lead to premature atherosclerosis and coronary
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
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B. Wolman Disease and Cholesteryl Ester Storage
Disease: Acid Lipase Deficiency
Lysosomal acid lipase (⫽acid cholesteryl ester hydrolase) is essential for the hydrolysis of cholesteryl esters and triglycerides in lysosomes. Mutations in the enzyme give rise to two clinical disorders: the severe infantile-onset Wolman disease and the milder late-onset
cholesteryl ester storage disease (CESD) (7, 10). Enzyme
activity is more dramatically reduced in Wolman disease,
⬃200-fold in Wolman disease fibroblasts compared with
50- to 100-fold reduction in cholesterol ester storage disease cells (27).
Wolman disease presents with hepatosplenomegaly,
steatorrhea, abdominal distension, adrenal calcification,
and failure to thrive during the first weeks of life and
usually leads to death before 1 yr of age. In contrast to
Wolman disease, CESD is relatively benign. Hypercholesterolemia and accumulation of neutral fats and cholesterol esters in the arteries predispose affected individuals
to atherosclerosis. Massive hepatomegaly and hepatic fibrosis may lead to esophageal varices (11).
Generation of lysosomal acid lipase-deficient mice
recapitulated the hepatosplenomegaly but not the shortened life span characteristic to severe acid lipase deficiencies in humans (52). In addition, the mouse model revealed an unanticipated role for the enzyme in adipocyte
differentiation, fat mobilization, and development of insulin resistance (53). At present, there is no cure for the
disease, but enzyme replacement therapy in the mouse
suggests that a similar strategy may be successful in
human acid lipase deficiencies (53, 54).
C. Niemann-Pick Type C Disease:
Egress of Cholesterol From Lysosomes
Niemann-Pick type C (NPC) disease is characterized
by the accumulation of unesterified cholesterol and other
lipids, in particular sphingolipids, in late endocytic organelles. This is accompanied by impaired cholesterol
esterification in the ER and defective suppression of cholesterol synthesis and LDLR activity (132, 176). The disease belongs to sphingolipid storage diseases in which
also Niemann-Pick type A and B diseases are classified,
being caused by primary deficiency of acid sphingomyelinase. Clinically NPC disease manifests as a progressive
neurodegenerative disorder with visceral involvement, including hepatosplenomegaly, and affecting an estimated
1:150,000 individuals. The vast majority of the cases are
caused by mutations in the late endosomal membrane
protein NPC1 (30), the rest (5%) being due to mutations in
a soluble lysosomal protein called NPC2/HE1 (163). Diagnosis is based on demonstration of decreased esterification of LDL-derived cholesterol in fibroblasts and cellular
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heart disease. The elevated serum cholesterol concentrations lead to a more than 50% risk of coronary heart
disease by age 50 in men and at least 30% in women aged
60 yr (219, 228). Aortic root disease is the most common
cardiac manifestation, and by puberty, the patients invariably have some degree of atheroma of the ascending aorta
(239). The primary clinical diagnostic criteria are an elevated cholesterol level (LDL-cholesterol in particular,
HDL-cholesterol is within the normal range or low), presence of tendon xanthomata in the patient or first degree
relative, and a dominant pattern of inheritance of premature heart disease or elevated cholesterol (80). Definite
diagnosis can be made by the identification of the mutation involved (for the LDLR, over 700 mutations have
been reported so far) (91). Currently, mutations are only
detected in 30 –50% of patients with a clinical diagnosis.
Some of these cases apparently represent mutations in
other, unidentified genes.
The treatment of FH has become significantly more
effective with the availability of statins (inhibitors of
HMG-CoAR) in 1989. Statins can reduce LDL-cholesterol
by ⬃50 – 60% in homozygous FH patients (141, 142). Combination of a statin with a bile acid sequestrant, fibrate
(PPAR␣ agonist that reduces hepatic triglyceride production by increasing fatty acid oxidation), or the cholesterol
absorption inhibitor ezetimibe often increases effectiveness of the therapy. In individuals nonresponsive for conventional drug treatment, repeated LDL-apheresis can be
performed.
A number of rare cases of an autosomal recessive
form of hypercholesterolemia have also been described.
All the ⬃50 cases reported worldwide appear to result
from mutations in ARH, a protein involved in the internalization of the LDLR via clathrin-coated pits (71, 222).
Failure of the liver to take up and degrade plasma LDL
leads to the increased plasma LDL cholesterol levels. The
structural features of ARH include a phospho-Tyr binding
domain for interaction with the endocytosis signal of the
LDLR, a domain for direct interaction with clathrin and a
phospholipid-phosphatidylinositol 4,5-bisphosphate-binding domain. Taken together, the data suggest that ARH
plays a role in gathering the LDLR into forming endocytic
carrier vesicles. Curiously, although the lack of LDLR
internalization is evident, e.g., in lymphoblasts and monocyte-derived macrophages, it is not manifested in skin
fibroblasts. This may be due to functional redundance
with potentially the homologous protein Disabled-2 taking over the function of ARH in fibroblasts (155, 159).
Overall, ARH patients appear to respond to lipid-lowering
medication more favorably than FH homozygotes, with
significant reduction in serum cholesterol by statins, bile
acid sequestrants, or their combination (8, 222). The
mechanistic reason for this better responsiveness to treatment compared with classic FH is unclear.
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D. Tangier Disease and Familial HDL Deficiency:
Efflux of Cholesterol From Cells
HDLs protect from the development of atherosclerosis, probably primarily by stimulating the removal of cholesterol from atherosclerotic lesion macrophages called
foam cells. It is now known that a macrophage plasma
membrane protein ABCA1 (ATP binding cassette transporter A1) plays a key role in the efflux of cholesterol to
lipid-poor apoA-I that is further lipidated to form HDL
(165). The importance of ABCA1 in this process was
unraveled by the identification of mutations in this gene
as the underlying cause of Tangier disease (20, 24, 196).
This rare disease is characterized by HDL deficiency,
sterol accumulation in tissue macrophages, and accelerated atherosclerosis. Remarkably, further studies have
indicated that a significant fraction (at least 10%) of more
common conditions with low circulating HDL levels can
be due to heterozygosity for mutations in ABCA1 (41, 68).
Heterozygosity for an ABCA1 mutation also predicted the
risk of ischemic heart disease in a population study (69).
The detailed molecular events involved in ABCA1mediated cholesterol efflux from macrophages are still
unresolved. It is clear that the protein promotes both
cholesterol and phospholipid efflux and that the two processes can be dissociated (235, 259). Close proximity of
apoA-I to ABCA1 as evidenced by chemical cross-linking
Physiol Rev • VOL
suggests that apoA-I binds to ABCA1 and that an optimal
conformation of ABCA1 facilitates the interaction (258).
ABCA1 mediates lipid efflux to apoA-I but not efficiently
to HDL. Instead, ABCG1 and SR-B1 can mediate further
cholesterol removal to more mature forms of HDL (73,
276). ABCA1 appears to release the lipids to the forming
nascent HDL on the cell surface, but endocytic circuits
contribute to ABCA1-mediated cholesterol efflux from
intracellular pools (38, 164). Functional cooperation between ABCA1 and NPC1 is suggested by the defective
ABCA1 induction in NPC1-deficient cells (39, 70) and the
observation that ABCA1-deficient cells have immobile,
lipid-laden late endosomes and altered NPC1 localization
(164).
The turnover of ABCA1 is rapid, and its expression
levels are highly regulated both at the transcriptional and
posttranslational level. ABCA1 gene expression is increased by activation of the heterodimeric transcription
factor LXR/RXR, and induction of ABCA1 expression is
likely to be critical in the antiatherogenic effects of LXR
ligands (241). ABCA1 protein can be proteolytically degraded by a thiol protease calpain, and apolipoprotein
binding stabilizes ABCA1 by decreasing this proteolysis
(256).
The role of ABCA1 in other tissues where it is
present, such as liver and intestine, is being intensively
investigated. A direct role in intestinal cholesterol absorption is unlikely based on its reported localization
on the basolateral membrane of enterocytes (160). In
the liver, ABCA1 promotes biliary cholesterol excretion
and may participate in apoB/VLDL secretion (250).
Tangier disease patients typically have reduced levels
of ApoB-containing lipoproteins (207). However, differences in hepatic ApoB production, lipid output, or
ApoB clearance rates do not seem to explain the phenomenon (4).
Several transgenic and knock-out mouse models to
investigate the role of ABCA1 at the whole body level
have been generated and recently reviewed (4, 109). It is
obvious that the genetic background of the mice greatly
influences the phenotype and probably explains many of
the discordant findings. However, common to all the
ABCA1-deficient homozygous mice is the absence of HDL.
Recent mouse studies have uncovered that hepatic
ABCA1 contributes to plasma HDL levels (187) and that
ABCA1 affects the hepatic phospholipidation and cholesterol acquisition of ApoA-I (278). Importantly, targeted
inactivation of ABCA1 in the liver showed that hepatic
ABCA1 is critical in maintaining plasma HDL levels (240);
direct lipidation of hepatic lipid-poor apoA-I by ABCA1 in
the Golgi and at the plasma membrane (143) slows ApoA-I
catabolism by the kidney and prolongs its plasma residence time.
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sterol/sphingolipid accumulation in late endocytic organelles by using fluorescent probes (104).
NPC1 contains a SSD, similarly to, e.g., SCAP and
HMG CoAR (46), but its functional role is not equally well
understood. Recent data show that introduction of mutations to the SSD that correspond to activating mutations
of SCAP, result in the stimulation of LDL-cholesterol trafficking to the plasma membrane and ER (153). NPC1 and
NPC2 are both capable of binding sterol, the former via
the SSD, the latter with an incipient cavity that apparently
dilates to accommodate the lipid (67, 115, 166). On the
basis of genetic evidence, NPC1 and NPC2 are likely to
function in the same pathway, but the precise roles of
both proteins remain unresolved (220). Interestingly,
studies in yeast reveal a role for NPC1 in the recycling of
sphingolipids (140), and in human subjects, sphingolipids
are more promising than cholesterol as targets for therapies aiming at substrate reduction (122).
Another promising avenue for therapy is the administration of neurosteroids. The rationale is the observed
deficiency of neurosteroids in the NPC1 mouse model and
the critical role of neurosteroids for several brain functions (83). Furthermore, LXR activation may offer yet
another possible option for treatment. This is based on
the reduced generation of oxysterols and defective
ABCA1-dependent lipid efflux in NPC cells (39, 70).
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
E. Sitosterolemia: Intestinal Sterol Absorption
F. Smith-Lemli-Opitz Syndrome and Other Inborn
Errors of Cholesterol Synthesis
Until now, seven inherited defects of cholesterol biosynthesis have been described in humans. Although they
are, strictly speaking, not primary cholesterol transport
defects, they are briefly summarized here because most
likely some of their characteristics result from the lack of
cholesterol and/or excess sterol precursors in the membrane. According to our recent results, even the immediPhysiol Rev • VOL
ate precursor of cholesterol, desmosterol, cannot substitute for cholesterol in cellular membranes (249). The
reader is referred to excellent reviews and references
therein for more comprehensive information on this
group of disorders (93, 179). The first disease identified
(in 1968), mevalonic aciduria due to a deficiency of mevalonate kinase, is the only disease identified in the presqualene portion of the cholesterol synthesis pathway
(100).
The most common of these diseases, with an estimated incidence of 1/10,000 –1/60,000, is Smith-LemliOpitz syndrome (SLOS). It is caused by a deficiency of
7-dehydrocholesterol reductase that catalyzes the reduction of 7-dehydrocholesterol to cholesterol in the final
reaction of cholesterol synthesis. The clinical spectrum of
this disease is amazingly broad, from severe cases with
multiple malformations, severe mental retardation, and
prenatal/neonatal death to individuals with only minor
physical or behavioral problems. Approximately 5% of the
mildest patients have normal intelligence.
Desmosterolosis and lathosterolosis are also due to
last or second to last steps of cholesterol synthesis and
have partial phenotypic overlap with SLOS. However,
only a few patients have been described. In general, the
earlier defects of postlanosterol cholesterol synthesis
[HEM (hydrops-ectopic calcification-moth eaten) dysplasia, X-linked chondrodysplasia punctata, and CHILD syndrome (congenital hemidysplasia with ichthyosiform
erythroderma or nevus and limb defects)] are clinically
more severe than the defects in the late steps. Disorganized bone and cartilage structure including dwarfism is
typical, possibly related to defective Hedgehog signaling
(see below), and most severely affects individuals with
HEM dysplasia.
Diagnosis of this group of defects is based on biochemical tests demonstrating elevations of accumulating
sterol intermediates. In spite of the fact that the diseases
are clearly enzyme deficiencies, their pathogenesis is not
well understood. Probably, the lack of cholesterol itself,
accumulation of toxic intermediates, abnormal feedback
regulation of cholesterol synthesis, and/or abnormal signaling via Hedgehog proteins contribute (93). It has been
noted that many of the malformations are consistent with
impaired Hedgehog function. Sonic Hedgehog plays a
central role in midline patterning and limb development,
Indian Hedgehog is important for bone mineralization,
and desert Hedgehog is involved in genital development
(105). Hedgehog contains a covalently attached cholesterol molecule, and its receptor, Patched, has a SSD analogously to key regulators of cholesterol transport/metabolism. Studies in SLOS and lathosterolosis cells indicate
that Hedgehog dysfunction is likely due to decreased
sterol levels rather than teratogenic effects of the precursors (44).
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The diet, at least non-Western type, contains typically
roughly equal amounts of cholesterol and plant sterols.
On the average, ⬃50% of the cholesterol is absorbed
compared with ⬍5% of plant sterols. A rare recessive
disorder of sterol absorption, sitosterolemia (also known
as phytosterolemia), has helped to shed light on the principles underlying this difference. The disease is caused by
mutations in either ABCG5 or ABCG8 (16, 125). Sitosterolemia patients absorb 15–20% of the dietary plant sterols.
Interestingly, they also absorb an abnormally high fraction of dietary cholesterol and excrete less cholesterol
into the bile than normal subjects. This results in severe
hypercholesterolemia in childhood, xanthomas, accelerated atherosclerosis, and premature coronary artery disease (114). Diagnosis is confirmed by showing increased
plasma and tissue levels of plant sterols (18, 198).
Ezetimibe effectively reduces plasma plant sterol levels in
sitosterolemia patients (200). Interestingly, ABCG8 polymorphisms may serve as genetic markers of cholesterol
absorption efficiency at the population level (156).
The loss of ABCG5/G8 in humans results in high
absorption of plant sterols both in humans (138, 199) and
in mice (274). However, the fractional absorption of dietary cholesterol is only moderately increased in humans
and not at all in mice (138, 199, 274). This suggests that
under conditions of low dietary cholesterol intake,
ABCG5/G8 does not have a major influence on the amount
of chylomicron cholesterol reaching the liver. The situation may be different under high dietary cholesterol intake as suggested by the upregulation of the transporter in
such conditions (16, 190). However, it is evident that
ABCG5/8 not only prevents the movement of the bulk of
plant sterols beyond the enterocyte but also facilitates
biliary secretion of cholesterol and other neutral sterols.
Overexpression of both ABCG5 and ABCG8 leads to a
fivefold increase in biliary cholesterol secretion and a
⬃50% reduction in the absorption of dietary cholesterol
(275). Thus the combined role of ABCG5/8 in hepatic and
intestinal sterol balance has to be taken into account
when explaining the clinical manifestations of sitosterolemia.
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The existence of naturally occurring or targeted
mouse mutations for most of the disorders will help in
studying disease pathogenesis. However, because of the
differences between human and mouse cholesterol processing, especially in transplacental and fetal sterol transport, the phenotypes may be strikingly different. For example, desmosterolosis mice exhibit a milder phenotype
than that described for human desmosterolosis patients
(179, 261).
G. Cerebrotendinous Xanthomatosis and Other
Defects of Bile Acid Synthesis
Physiol Rev • VOL
H. Congenital Lipoid Adrenal Hyperplasia:
Transport of Cholesterol for Steroidogenesis
Mutations in the mitochondrial cholesterol transporter protein StAR cause congenital lipoid adrenal hyperplasia (lipoid CAH) (128). This rare, recessively inherited and potentially lethal condition results from an almost complete inability to synthesize steroids. The
condition is accompanied by the presence of large adrenals containing extremely high levels of cholesterol and
cholesteryl esters. The patients present with a severe
salt-losing syndrome (hyponatremia, hyperkalemia) and
failure to thrive that is fatal if not treated in early infancy
(227). Mineralocorticoid and glucocorticoid replacement
therapy is vital and may allow survival to adulthood.
In addition, all the affected individuals are phenotypic females irrespective of gonadal sex. Deficient fetal
testicular steroidogenesis in patients with a 46,XY karyotype results in phenotypically female genitalia (227). This
is because androgens are required for normal sexual male
differentiation, whereas the fetal ovary does not make
steroids during embryonic or early postnatal life. However, at puberty the ovary starts to synthesize steroids in
response to gonadotropins. Lipoid CAH 46,XX patients
may undergo normal feminization, presumably as a result
of StAR-independent steroid synthesis but have anovulation and ovarian cysts (209). A late-onset form of lipoid
CAH has been described as a result of a heterozygous
mutation in the P450scc gene (234).
It has been proposed that the congenital lipoid adrenal hyperplasia phenotype is the result of two separate
events (“two-hit model”): the first hit is the genetic loss of
steroidogenesis upon defective transfer of cholesterol to
the inner mitochondrial membrane, and the second hit is
the secondary interference with cellular processes by the
accumulation of steryl esters (22). StAR expression is
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Inborn errors of bile acid metabolism are here discussed only in relation to the enzymes that participate in
the early, rate-limiting steps of bile acid synthesis from
cholesterol, whereas distal defects in bile acid synthesis
and bile acid transporter defects are not included.
Cerebrotendinous xanthomatosis is caused by mutations in CYP27A, the rate-limiting enzyme in the acidic
pathway of bile acid synthesis (28). Enzyme deficiency
leads to impaired oxidation of the cholesterol side chain
in the formation of cholic acid (218). The accumulating
metabolite is cholestanol, the 5␣-dihydro derivative of
cholesterol. Disease diagnosis is made by demonstrating
cholestanol in abnormal amounts in the serum and tendon
of affected persons. Plasma cholesterol concentrations
are low normal. Patients develop multiple abnormalities,
including neurological symptoms, cataracts, diarrhea,
xanthoma, and atherosclerotic vascular disease (158).
The excess production and consequent accumulation of
cholestanol appears to play an important role in the disease pathophysiology (152). In addition, the lack of 27hydroxycholesterol may be relevant. Low levels of this
endogenous LXR ligand may stimulate foam cell formation. Moreover, the oxysterol may itself serve as a form of
sterol effluxed from cholesterol-laden cells (263). The
most effective therapy is supplementation with the missing end product of the pathway, chenodeoxycholic acid
(158).
In mice, disruption of sterol 27-hydroxylase gene
leads to hepatomegaly and dysregulation of hepatic cholesterol, bile acid, and fatty acid metabolism. However,
the mice lack most of the clinical and biochemical abnormalities characteristic to cerebrotendinous xanthomatosis (55, 193). This is probably because in Cyp27⫺/⫺ mice,
classic bile acid biosynthesis is not stimulated as much,
and the formed bile alcohols are more efficiently metabolized compared with the human patients (99).
The first human mutations in the enzyme initiating
the classical pathway of bile acid synthesis, CYP7A1, have
recently been described (183). A family with homozygous
mutations of 7␣-hydroxylase presented with a phenotype
reminiscent of that in familial hypercholesterolemia, with
elevated LDL associated with premature atherosclerotic
heart disease. In addition, the homozygotes had an increased hepatic cholesterol content, deficient bile acid
excretion, and signs of upregulation of the alternative bile
acid pathway. Some individuals had hypertriglyceridemia
and premature gallstone disease. Importantly, heterozygotes were also hyperlipidemic, indicating a codominant
disorder, and suggesting that variations in CYP7A1 gene
might contribute to the prevalence of atherogenic hyperlipidemia and cholesterol gallstone disease at the population level (183). Further studies are needed to identify
other families with this disorder. Notably, targeted disruption of CYP7A1 in mice yielded a complex phenotype
with conflicting results regarding serum lipids (205),
whereas mice overexpressing the protein were protected
from diet-induced atherosclerosis and gallstone formation (157).
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
limited to steroidogenic cells, but the protein belongs to a
large family of StAR-related lipid transfer (START)-domain proteins (5). Presumably, widely expressed STARTdomain proteins may deliver cholesterol to mitochondria
in other tissues. The ligands of this protein family also
include phospholipids and ceramides, but at least two
other proteins, MLN64 and STARD5, bind cholesterol
(192, 244).
The StAR knockout mouse recapitulates all the essential features of the corresponding human disease, including female external genitalia, failure to thrive, lipid
deposits in the adrenal cortex, and responsiveness to
corticosteroid replacement therapy (29, 90).
The assembly and secretion of triglyceride-rich lipoproteins require apoB and the ER localized cofactor
microsomal triglyceride transfer protein (MTP). Hypobetalipoproteinemia (i.e., low level of lipoproteins with
␤-electrophoretic mobility) is a condition characterized
by low plasma total cholesterol, low LDL cholesterol, or
low apolipoprotein B (apoB) levels. A number of factors,
such as illness or strict vegan diet, may result in low
apoB/LDL levels. Primary causes include abetalipoproteinemia and chylomicron retention disease, two recessively inherited traits, as well as familial hypobetalipoproteinemia, an autosomally dominantly inherited condition.
Abetalipoproteinemia is due to mutations in MTP
(264). MTP is a soluble protein in the ER lumen that
transfers neutral lipids (in particular cholesteryl esters
and triglycerides) as well as phospholipids to the forming
apoB-containing lipoproteins, i.e., chylomicrons in enterocytes and VLDL in hepatocytes (Fig. 3). MTP contains
a dimeric complex of protein disulfide isomerase (PDI)
together with a unique 97-kDa subunit. Abetalipoproteinemia causing MTP mutations are found in the 97-kDa subunit, and the disulfide isomerase activity of PDI is not
required for MTP transfer activity (254). Deficiency of
MTP activity leads to a defect in the production of both
chylomicrons and VLDL. Clinically it is manifested initially as malabsorption at first postnatal months, developing to fat-soluble vitamin deficiencies, and gradually to
neuroretinal and hematological complications. The condition is managed by lipid-poor diet containing essential
fatty acids in vegetable oil and supplementation of fatsoluble vitamins (17).
In mice, a homozygous MTP knockout is embryonically lethal (184). Conditional knockouts have been generated and found to mimic aspects of the human condition (31, 185), although evidently plasma apoB48/apoB100
levels in mice are not determined similarly as in humans.
In contrast to abetalipoproteinemia, the majority of
familial hypobetalipoproteinemia patients are asymptomPhysiol Rev • VOL
atic heterozygote cases due to gene defects, often missense or frameshift mutations, in apoB (204). The frequency of familial hypobetalipoproteinemia attributed to
truncated apoB has been estimated at 1 in 3,000 (262). The
individuals are resistant to atherosclerosis and in the
homozygous condition resemble abetalipoproteinemia.
Chylomicron retention disease and Anderson disease
are caused by mutations in the small GTPase Sar1b (108)
(Fig. 3). These conditions are manifested as severe malabsorption and failure to thrive in infancy, with deficiency
of fat-soluble vitamins. Affected individuals accumulate
chylomicron-like particles in membrane-bound compartments of enterocytes and have selective absence of chylomicrons in blood. All the mutations identified are in
SARA2, the protein encoding Sar1b, and all the missense
mutations map to the nucleotide binding site of the protein (211). The exchange of GTP for GDP on Sar1 is
known to initiate the budding of COPII-coated ER-toGolgi transport vesicles (9, 202). The finding of Sar1b
mutations revealed the requirement for Sar1b in the intracellular transport of chylomicrons. The precise role of
COPII in the process remains to be solved: chylomicrons
may actually leave the ER in COPII-coated vesicles or
COPII may just be needed to recruit additional machinery
needed for chylomicrons to mature along the secretory
pathway (232, 277).
VI. CELLULAR CHOLESTEROL BALANCE
AS A TARGET FOR CARDIOVASCULAR
PHARMACOLOGY
Current therapeutic strategies to prevent atherosclerosis are largely based on the use of statins, which inhibit
the rate-limiting enzyme of cholesterol biosynthesis,
HMG-CoA reductase, and decrease serum LDL cholesterol levels (65). In addition, statins improve endothelial
function, e.g., by restoring NO production, enhance the
stability of atherosclerotic plaques, and decrease inflammation and oxidative stress (127). The effectiveness of
statins in reducing coronary morbidity and mortality is
well established. However, the contribution of synthesis
versus absorption in whole body cholesterol balance varies between individuals (87) and in persons exhibiting a
poor response in cholesterol lowering with statins; therapy with a selective cholesterol absorption inhibitor,
ezetimibe, may be more effective. This is based on the
idea that in statin nonresponders, de novo cholesterol
synthesis is probably low and the contribution of cholesterol absorption for cholesterol levels is more substantial.
Importantly, ezetimibe can be used in combination with
statin, and coadministration results in an incremental decrease in LDL-cholesterol (13, 56). Ezetimibe targets
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I. Hypobetalipoproteinemias: Defects
of Lipoprotein Assembly
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ELINA IKONEN
VII. CHOLESTEROL-SPHINGOLIPID RAFTS:
IMPLICATIONS FOR HUMAN DISEASE
The medical importance of lipid rafts in the pathogenesis of diseases is now well appreciated (213). The
Physiol Rev • VOL
cholesterol dependence of rafts is typically addressed by
pharmacological cholesterol depletion. However, instead
of decreased cholesterol levels, the vast majority of diseases with intracellular cholesterol transport problems
lead to cholesterol deposition or subcellular cholesterol
imbalance. The preferred subcellular site(s) of the deposition vary as probably do the compensatory changes
taking place in other lipids and proteins. Notably, the
intracellular cholesterol imbalance will probably not manifest only at the initial site of the defect. For instance, a
defect in cholesterol biosynthesis may lead to endosomal
sterol deposition (260). Interestingly, connections between the maintenance of cholesterol-sphingolipid rafts
and intracellular cholesterol transport are also starting to
emerge.
It has been proposed that cholesterol-sphingolipidoses may lead to the jamming of rafts in the endolysosomal
compartments (131, 214). In NPC fibroblasts, newly hydrolyzed LDL-cholesterol is indeed incorporated more
avidly into detergent-resistant membranes than in control
fibroblasts (136). Interestingly, recent evidence suggests
that NPC cells with massive cholesterol deposition, such
as primary hepatocytes from the NPC mouse, also have
excess cholesterol in the plasma membrane (248). Moreover, this inhibits raft-dependent signaling as evidenced
by defective insulin receptor activation and its restoration
upon plasma membrane cholesterol depletion (248).
Thus, in a cholesterol transport defect, excess cholesterol
is clearly detrimental to raft-dependent signaling.
For understanding raft-dependent human diseases,
the site(s) of altered cholesterol concentration, whether
in the circulation or at the cellular level, e.g., in the plasma
membrane, endosomes, or lipid droplets, is clearly important. This is exemplified by the multitude of findings
concerning cholesterol levels and proteolysis of amyloid
precursor protein (APP), a critical process in the development of Alzheimer’s disease (AD). Initially, a link between cholesterol and AD was established by the finding
that the allele ⑀4 of apoE predisposes to an early onset of
AD (45). ApoE plays an important role in cholesterol
balance and regenerative processes in the brain (146,
252). Later on, genetic variants of a number of other key
players of cholesterol transport, including ABCA1,
ABCA2, and ACAT, have been reported as modifiers of AD
risk (112, 139, 266). Epidemiological evidence shows that
treatment of hypercholesterolemic individuals with statins
lowers the incidence of AD (12, 107, 267). However, the
most commonly used statins do not penetrate the bloodbrain barrier efficiently (223), and subjects treated with
statins do not show major changes in brain membrane
cholesterol (61). It is therefore possible that the beneficial
effects of statins in AD are not due to their effects on
neuronal rafts.
Nevertheless, the neuronal cholesterol content and
distribution clearly have an effect on amyloid peptide
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NPCL1 in the enterocytes where it reduces the absorption
of dietary and biliary cholesterol by preventing its absorption through the intestinal wall (175). It also prevents the
absorption of noncholesterol sterols, such as plant sterols, but has no effect on the absorption of fat-soluble
vitamins, fatty acids, or bile acids.
Other strategies to inhibit cholesterol absorption are
the use of bile acid sequestrants or PPAR ␣-agonists
(fibrates) in patients with elevated triglyceride levels (57).
The use of plant sterol or stanol-enriched margarine is
based on the inhibition of dietary and biliary cholesterol
uptake by competing with cholesterol for incorporation
into mixed micelles (88).
Among the most promising antiatherogenic approaches under development are agonists of nuclear hormone receptors, in particular LXR, which controls the
expression of key regulators of cholesterol transport such
as the ABC transporters ABCA1, G1, G4, G5, G8, the
ApoCI/CII/CIV gene cluster, as well as lipoprotein-modifying enzymes, e.g., lipoprotein lipase, cholesteryl ester
transfer protein, and phospholipid transfer protein (241).
Evidence for LXR agonist-induced stimulation of reverse
cholesterol transport from macrophages to feces was recently provided using several mouse models (162). In
addition, ACAT inhibitors are being evaluated in clinical
trials as potential compounds inhibiting foam cell formation and atherosclerotic lesion development (226). Other
lipid-lowering agents under development including cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, ileal
bile acid transport (IBAT) inhibitors, and dual PPAR ␣and ␥-agonists, are discussed in more detail elsewhere
(60, 111).
Conspicuously, a number of compounds developed
for other purposes have adverse effects on cellular cholesterol trafficking that may be related to their potential
side effects. These include psychopharmaca such as the
tricyclic antidepressant imipramine that inhibits intracellular cholesterol transport in a manner mimicking the
Niemann-Pick type C phenotype (124, 246) and the antifungal agents nystatin and amphotericin B that are known
to disrupt caveolae (194). Finally, some compounds affecting cholesterol metabolism, such as the late-stage
cholesterol biosynthesis inhibitor triparanol, have severe
teratogenic effects resulting in a phenotype that shares
characteristics with inborn errors of postlanosterol cholesterol biosynthesis. The triparanol-induced limb anomalies were shown to originate from altered signaling via
the sterol-bound morphogen Hedgehog (77).
DISEASES OF CELLULAR CHOLESTEROL TRANSPORT
simple to make, and disease characteristics cannot be
deduced from the expression pattern of a protein. Rather,
symptoms are likely to appear from those tissues in which
compensatory mechanisms or parallel pathways fail. An
important challenge for the future is to understand how
subtle alterations in cholesterol transport and metabolism, perhaps over the span of decades, contribute to the
pathogenesis of chronic diseases in the population. It
seems evident that besides, and sometimes instead of, few
major loci underlying genetic predisposition to cellular
cholesterol disturbances, we need to search for multiple
variants with modest effects. This necessitates large-scale
genetic and environmental epidemiology in human populations. In parallel, we need to develop experimental strategies to study cholesterol trafficking in model organisms
and to bridge the gap between cell analyses and in vivo
tissue biology.
ACKNOWLEDGMENTS
VIII. CONCLUSIONS AND PERSPECTIVES
During the past decade, we have undoubtedly witnessed the “single gene/protein era” of intracellular cholesterol transport. The molecular link between StAR and
congenital lipoid adrenal hyperplasia was discovered
more than 10 years ago, and during the years to come, an
increasing number of proteins mutated in monogenic human diseases have been identified. A major breakthrough
in the field was the identification of ABCA1 as the Tangier
disease gene. This has played an important contribution
in the development of new pharmacological antiatherogenic strategies and underscored the fundamental importance of ABC transporters in cholesterol trafficking. On
the other hand, the identification of NPC1L1 as the target
of ezetimibe serves as an example of how basic research
findings may help to validate the use of existing pharmacological regimen.
The leap from the defective protein to the next steps,
solving the molecular structures and uncovering protein
interaction networks, has been successfully initiated in a
number of cases but will probably be more challenging
with this group of gene products than with some others.
In experimental strategies, the lipophilic nature of the
proteins will continue to do tricks on us, but the advancement of tools, such as genome-wide RNAi approaches for
finding functionally linked proteins and tissue-specific
knockouts of proteins of interest, will increase capacity
and precision. Transcriptional regulators as major
switches for groups of proteins in the same or related
pathways will play an important role in attempts to orchestrate the cellular cholesterol transport machineries.
From the pathophysiological point of view, the spectrum of affected tissues is crucial and at times unexpected, considering the available knowledge at the cellular level. Genotype/phenotype correlations are often not
Physiol Rev • VOL
I thank members of my lab for helpful discussions, anonymous reviewers for insightful comments on the manuscript, and
the Editorial Board (Ole Petersen) for patience during the manuscript preparation.
Address for reprint requests and other correspondence: E.
Ikonen, Institute of Biomedicine/Anatomy, Univ. of Helsinki,
Haartmaninkatu 8, FIN-00014 Helsinki, Finland (e-mail:
[email protected]).
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86 • OCTOBER 2006 •
www.prv.org