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First published online August 24, 2007
doi: 10.1242/10.1242/dev.004408
Review |
1 Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10,
D-13125 Berlin, Germany.
2 Max Planck Institute of Molecular Cell Biology and Genetics,
Pfotenhauerstrasse 108, D-01307 Dresden, Germany.
* e-mails: willnow{at}mdc-berlin.de; eaton{at}mpi-cbg.de
SUMMARY
Previously, the relevance of lipoproteins and their receptors has mainly been discussed in terms of cholesterol clearance in the adult organism. Now, findings from nematodes to fruit flies to mammals all point towards novel and unexpected roles for lipoprotein metabolism in the control of key regulatory pathways in the developing embryo, including signaling through steroid hormones and throughout the hedgehog and Wnt signaling pathways. Here, we discuss the emerging view of how lipoproteins and their receptors regulate embryogenesis.
Introduction
All lipids transported in the plasma or extracellular fluid of
multicellular organisms are solubilized by specialized transport particles, of
which the most common are lipoproteins (see
Box 1 for details).
Lipoproteins traffic lipids such as cholesterol from the tissue of origin to
target sites, where the lipid cargo is delivered via lipoprotein
receptor-mediated uptake (Havel and Kane,
2001
). So far, the biological significance of lipoproteins has
mainly been discussed in terms of cholesterol homeostasis in the adult
organism. Here, lipoproteins regulate the supply of the sterol required for
many cellular activities, including membrane formation, the synthesis of
steroid hormones and the post-translational modification of proteins (for
example, the activation of hedgehog)
(Havel and Kane, 2001) (see
Box 2 for details). Our focus
on adult lipoprotein metabolism has chiefly been guided by its importance as a
risk factor for cardiovascular disease. Disturbances in lipoprotein metabolism
in patients may result in dramatic increases in plasma cholesterol levels
(hypercholesterolemia) and, consequently, in atherosclerosis and premature
death from coronary artery disease
(Goldstein et al., 2001).
Early on, evidence implied that lipoproteins have an equally important yet
poorly understood function in embryonic development; evidence that has come
from humans and experimental animal models with metabolic malformation
syndromes, in which the pharmacological or genetic inactivation of key factors
in cholesterol and lipoprotein metabolism causes developmental anomalies
(reviewed by Kelley, 2000).
These syndromes include inborn errors in cholesterol biosynthesis, such as
Smith-Lemli-Opitz syndrome (SLOS), in which mutations in the gene encoding
7-dehydrocholesterol reductase (DHCR7) cause cleft palate and
holoprosencephaly (Fitzky et al.,
1998); mevalonic aciduria, a defect of mevalonate kinase, which
causes facial dysmorphology and skeletal dysplasia
(Hoffmann et al., 1993); as
well as desmosterolosis, a malfunction of desmosterol reductase, which is
associated with macrocephaly, ambiguous genitalia and short limbs
(FitzPatrick et al., 1998).
Also, the targeted inactivation of genes in lipoprotein metabolism, such as
those encoding apolipoprotein B (APOB)
(Farese et al., 1995),
microsomal triglyceride transfer protein
(Raabe et al., 1998) and the
lipoprotein receptor LRP2 (Willnow et al.,
1996), cause developmental abnormalities in mice, in particular
brain formation defects. Not surprisingly, the favored hypothesis to explain
these defects has been guided by our view of adult lipoprotein metabolism, in
as much as insufficient levels of cholesterol in embryonic tissues were
considered to be at the heart of the problem.
Box 1. Cell biology of lipoproteins
Lipoproteins are spherical macromolecules of 10-1200 nm diameter. They are composed of a core of neutral lipids that include mostly cholesterol ester and triglycerides but also fat-soluble vitamins. The core of the particle is surrounded by an amphipathic shell of polar phospholipids and cholesterol. The density of lipoproteins is inversely related to their size and reflects the unique composition of the lipid core. Accordingly, they are categorized into six classes, including high-density (HDL), low-density (LDL) and very low-density lipoproteins (VLDL). Embedded in the shell of lipoproteins are specialized apoproteins, such as apolipoproteins in vertebrates (e.g. APOB and APOE), apolipophorines in insects, as well as vitellogenins in all egg-laying species. The apoproteins play decisive roles in the cell biology of lipoproteins. Some are required for the assembly and secretion of the particles from donor tissues, a process that takes place in the rough endoplasmic reticulum (ER) and involves the activity of lipid transfer proteins such as the vertebrate microsomal triglyceride transfer protein (MTP) (see figure). MTP lipidates the nascent polypeptide chain of APOB that is co-translationally transported into the lumen of the ER. A primordial particle is formed that further increases in lipid content to transform into a mature lipoprotein, which is secreted via the secretory pathway of the cell. Other functions of apoproteins involve the interaction with enzymes (e.g. lipases) that modify the lipid content of circulating lipoproteins. Finally, some apoproteins interact with lipoprotein receptors to deliver the lipid cargo to target cells. Receptor interaction results in the endocytic uptake and lysosomal catabolism of the particles, as with LDL. Alternatively, lipids can be extracted from the lipoproteins that are attached to their receptors on the cell surface, as with vertebrate HDL and insect lipophorins.
|
| Box 2. Main functions of lipoproteins The main role of lipoproteins is to transport structural and nutritional lipids throughout the organism. This function is conserved throughout evolution. Thus, lipoproteins are formed in tissues that absorb lipids from the diet or that serve as a major lipid storage pool in the organism (the fat body in insects, the liver in vertebrates). Following release into circulatory fluids, lipoproteins deliver their cargo to target tissues that require these lipids. Lipoprotein-bound triglycerides serve as an energy source, whereas cholesterol is a component of cell membranes and is required for steroid hormone and bile acid synthesis. In addition, lipoproteins also have more specialized functions in lipid homeostasis. Vitellogenins are lipoproteins that are formed in all egg-laying species. They deliver yolk lipid to the oocyte prior to egg deposition. High-density lipoproteins (HDL) are particles secreted from peripheral tissues that shuttle excessive lipids back to the liver for deposition. In humans, this so-called `reverse cholesterol transport' counteracts the accumulation of cholesterol in vessel walls and the formation of atherosclerotic plaques.
|
One example that illustrates the shortcomings of this concept is
holoprosencephaly (HPE), a midline defect that is characterized by the fusion
of the forebrain hemispheres. HPE is the most common developmental forebrain
anomaly in humans, affecting as many as 1 in 250 pregnancies
(Wallis and Muenke, 2000). In
mice, craniofacial abnormalities consistent with HPE are caused by mutations
in the gene that encodes Dhcr7 (as in human SLOS)
(Fitzky et al., 2001;
Wassif et al., 2001), in sonic
hedgehog (Shh) (Chiang et al.,
1996) and also in Lrp2
(Willnow et al., 1996).
Accordingly, the inadequate supply of cholesterol from endogenous biosynthesis
or from maternal sources absorbed via the yolk sac was believed to be
responsible for hampering the formation of cell membranes or the activation of
SHH, a regulator of forebrain patterning. However, this hypothesis has been
challenged by a number of observations. For example, cholesterol levels are
normal in approximately 10% of all SLOS patients
(Kelley and Hennekam, 2000).
Also, cholesterol-mediated activation of SHH is not impaired in murine models
of the disease (Cooper et al.,
2003). Finally, sustained expression of LRP2 in the murine yolk
sac does not rescue Lrp2-null mice from forebrain malformations
(Spoelgen et al., 2005).
This left the puzzling question of what the true contribution of lipoprotein metabolism to embryonic development might be. The surprising answer came with the findings of recent studies that pointed towards lipoproteins and their receptors having unexpected roles as mediators of embryonic signaling pathways.
This review discusses the emerging view that lipoproteins actively participate in signaling pathways by regulating the distribution and local delivery of key regulators of cellular differentiation processes, such as sterols and lipid-linked morphogens. These findings provide a new paradigm in developmental biology that is certain to revise the current perception of lipoproteins as mere cargo transporters of membrane cholesterol.
Lipoprotein receptors are essential for embryonic development
Major advances in our understanding of embryonic lipoprotein metabolism
have come from animal models in which dysfunctional members of the LDL
receptor gene family have given rise to developmental defects. The LDL
receptor gene family represents the main class of endocytic lipoprotein
receptors, which are expressed in many tissues in organisms as distantly
related as nematodes and mammals (Fig.
1). The LDL receptor is the archetypal member of the family and
has structures that are representative of a receptor involved in cellular
cholesterol uptake (Fig. 2A).
The significance of this receptor for systemic cholesterol homeostasis is
underscored by the pathological features of patients who suffer from familial
hypercholesterolemia (FH). FH is caused by heritable LDL receptor gene defects
and results in the inability of individuals to clear cholesterol-rich LDL from
the blood stream, leading to excessive levels of circulating cholesterol
(Goldstein et al., 2001).
These features are shared by models of LDL receptor deficiency in mice and
rabbits (Table 1).
|
;
Nykjaer and Willnow, 2002). In
some instances, linking developmental defects to impaired lipoprotein
metabolism was obvious, as with mutations in genes that encode vitellogenin
receptors. Loss of receptor activity in C. elegans rme-2 mutants
(Grant and Hirsh, 1999), in
Drosophila yolkless (yl)
(Schonbaum et al., 1995) and
in the chicken restricted-ovulator strain
(Bujo et al., 1995) prevents
the deposition of yolk (vitellogenesis), so causing female sterility. By
contrast, the abnormal layering of neurons in the cortex and cerebellum of
mouse models with very low-density lipoprotein receptor (VLDLR) and
apolipoprotein E receptor 2 (APOER2; also known as LRP8 - Mouse Genome
Informatics) deficiencies has unambiguously been linked to a defect in the
binding and transmembrane signaling of reelin, a secreted factor that provides
guidance cues to migrating neurons in the developing brain
(Bock and Herz, 2003;
Hiesberger et al., 1999;
Trommsdorff et al., 1999).
There is no evidence to suggest that lipids are involved in the latter
phenomenon. However, there are yet other members of the gene family that
impact on embryogenesis, as judged from the developmental abnormalities seen
in gene-targeted mice (Table
1). In these cases, regulatory roles for lipoproteins and their
lipid cargo remained a hypothesis to be explored. For example, disruption of
the Lrp1 gene causes lethality of affected embryos around
mid-gestation (Herz et al.,
1993), defects that are possibly linked to impaired formation of
the liver (Roebroek et al.,
2006). Mice deficient for Lrp6 suffer from axial
truncation and abnormal head and limb structures
(Pinson et al., 2000), whereas
Lrp4-/- mice have more-specific defects in late
embryogenesis that affect limb formation
(Johnson et al., 2005).
Finally, the development of the forebrain and reproductive organs is impaired
in Lrp2-deficient mouse embryos, phenotypes that are partially
recapitulated in models of impaired cholesterol biosynthesis.
|
|
Nematodes express several receptors of the LDL receptor gene family,
including RME-2 and C. elegans LRP-1 (Ce-LRP-1). RME-2 is a typical
vitellogenin receptor that is expressed in oocytes and that mediates the
endocytic uptake of yolk, a lipoprotein particle that consists of
vitellogenins complexed with intestine-derived lipids. Loss of receptor
activity in rme-2 mutants causes impaired vitellogenesis and reduced
embryonic survival (Grant and Hirsh,
1999). These findings are consistent with a role for lipoprotein
metabolism in the supplementation of the fertilized oocyte with lipids prior
to egg deposition, a function conserved throughout evolution
(Box 2,
Table 1). Perhaps more
rewarding in terms of conceptual advances has been the analysis of a second
lipoprotein receptor in C. elegans, Ce-LRP-1, the homolog of LRP2
(megalin) in mammals (Yochem and
Greenwald, 1993). Ce-LRP-1 is strongly expressed on the apical
surface of the hypodermis, which comes into contact with the worm's
environment. Recessive mutations in ce-lrp-1 produce a complex
phenotype, involving arrested larval growth and the inability to shed the old
cuticle during molting (Yochem et al.,
1999). Although the exact mechanism that underlies these
phenotypes remains obscure, two additional observations are remarkable. The
larval growth arrest phenotype in ce-lrp-1-deficient larvae resembles
features observed in dauer (enduring), a specialized diapause stage of L3
larvae that is induced by hostile conditions, such as starvation or high
population density. Furthermore, ce-lrp-1-deficient phenotypes could
be reproduced in the wild-type larvae by cholesterol depletion, implicating
defects in cholesterol homeostasis in the mutant phenotype. Because nematodes
are auxotrophic for cholesterol, which they take up from the environment
through the hypodermis, these findings indicate an obvious role of Ce-LRP-1 in
supplementing nematodes with the sterol from the environment
(Yochem et al., 1999). But
what conceptual advances in our understanding of cholesterol metabolism and
its role in larval development have emerged from these studies? The surprising
twist came from studies by Kurzchalia and colleagues, who uncovered why
nematodes need cholesterol (Matyash et
al., 2004). They demonstrated that reproductive growth in
nematodes requires an intracellular steroid hormone, tentatively termed
gamravali, that inhibits the activity of the nuclear hormone receptor DAF-12
(Fig. 2B). In the presence of
gamravali, the DAF-12-dependent program to undergo diapause is blocked and
normal larval growth ensues. Although not proven formally, the resemblance
between ce-lrp-1 mutants and sterol-depleted larvae strongly suggests
a model in which the precursor cholesterol is specifically delivered to target
cells via the lipoprotein receptor Ce-LRP-1, enabling the formation of
intracellular steroid hormones that regulate dauer larvae formation and
molting (Fig. 2B)
(Entchev and Kurzchalia, 2005;
Matyash et al., 2004). Support
for this model comes from studies by Grigorenko et al., who demonstrated that
loss of the polytopic endoprotease Ce-IMP-2, which is related to mammalian
presenilins, also results in larval growth arrest and molting phenotypes.
Ce-IMP-2 is proposed to perform regulated intramembranous cleavage of
Ce-LRP-1, liberating the intracellular domain of the receptor in response to
ligand binding (Grigorenko et al.,
2004). However, whether and how possible signals through the
receptor tail regulate steroid hormone signaling is still a matter of
debate.
|
; Wojtal et al.,
2006). Lipoprotein receptors deliver androgens and estrogens
A role for lipoprotein receptors in the cell-type-specific delivery of steroid hormone signals during development has also been confirmed in mice.
Lrp2 is highly expressed in a number of absorptive epithelia,
including yolk sac, neural tube, kidney and reproductive organs of the
mammalian embryo. In addition to other abnormalities
(Table 1),
Lrp2-deficient mice suffer from defects in the maturation of
reproductive organs, including maldescent of the testis in males
(cryptorchidism) and impaired opening of the vaginal cavity in females
(Hammes et al., 2005). These
features are reminiscent of rodents treated with anti-androgens and
antiestrogens during the embryonic or postnatal period of life, respectively
(Ashby et al., 2002;
Spencer et al., 1991),
implicating impaired sex steroid signaling in the phenotypes of Lrp2
mutant mice. A clue to understanding the role of LRP2 in the embryonic
development of reproductive organs has come from studies on the function of
the receptor in the adult kidney (Nykjaer
et al., 1999). These studies demonstrated that LRP2 mediates the
retrieval of the steroid 25-hydroxyvitamin D3 from the primary
urine into cells of the renal proximal tubules, the major cell type in the
body that is responsible for the conversion of this inactive precursor into
the biologically active steroid hormone 1, 25-dihydroxyvitamin D3.
Intriguingly, cellular uptake of 25-hydroxyvitamin D3 does not
proceed by the non-specific diffusion of the free steroid through the plasma
membrane as postulated in the free hormone hypothesis
(Mendel, 1989). Instead, this
uptake involves receptor-mediated endocytosis of 25-hydroxyvitamin
D3 bound to its plasma carrier, the vitamin D binding protein (DBP;
also known as GC globulin - Mouse Genome Informatics)
(Nykjaer et al., 1999).
Similarly, LRP2 was also found to be required for the cell-type-specific
uptake of androgens and estrogens complexed with the sex hormone binding
globulin (SHBG) (Hammes et al.,
2005) (Fig. 3). The
latter observation suggested a model in which tissues in the reproductive
tract of Lrp2-/- embryos fail to specifically acquire
carrier-bound sex steroids, resulting in impaired action of androgens and
estrogens, despite normal circulating levels of these hormones.
Developmental processes that regulate testicular descent in male embryos
provide a molecular explanation for LRP2 action. During late gestation, the
male gonad migrates from the lower kidney pole into the inguinal region (close
to the bladder neck), completing the first step towards ultimate descent into
the scrotum. This initial movement of the male gonad is critically dependent
on the differential fate of two tissues of the genital mesentry that attach to
this organ: the growth of the gubernaculum and the regression of the cranial
suspensory ligament (CSL) (Heyns and
Hutson, 1995). The gubernaculum attaches to the caudal end of the
gonad and tracts it towards the bladder neck. By contrast, the CSL attaches to
the cranial pole of the testes, tethering them to the dorsal abdominal wall.
Regression of the CSL in males is essential to enable descent of the testes
and depends on exposure of its primordium to fetal testicular androgens
(van der Schoot and Elger,
1992). Lrp2 mutant male embryos fail to induce regression
of the CSL, a defect known to cause cryptorchidism
(van der Schoot and Elger,
1992; Zimmermann et al.,
1999). In wild-type mice, expression of Lrp2 is seen in
the epithelium of the mesonephric tubules in close proximity to the primordium
of the CSL, indicating the involvement of the receptor in the spatially and
temporarily restricted uptake of androgens into target tissues that are
responsible for inducing CSL regression
(Fig. 3).
|
As well as trafficking signaling sterols, lipoproteins have recently also
been shown to bear an unexpected protein cargo: lipid-linked morphogens of the
hedgehog (Hh) and Wnt families
(Panáková et al.,
2005). The association of both Hh and the Wnt family protein
Wingless (Wg) with lipoproteins has important consequences for imaginal disc
development in Drosophila. The Drosophila lipoprotein
Lipophorin is made in the fat body, a tissue that has functions similar to
those of the vertebrate liver and adipose tissue. The apolipoprotein moiety of
these particles, Apolipophorin (also known as Retinoid- and fatty-acid binding
protein - Flybase), is a member of a large conserved family of lipid binding
proteins that include APOB, the protein that represents the structural
scaffolds of most lipoprotein particles in vertebrates
(Shelness and Ledford, 2005)
(see Box 1). These particles
circulate through the larval hemolymph to the developing imaginal tissues,
where they become associated with both Wg and Hh by an active process that is
not yet fully understood. Lowering the systemic level of Lipophorin particles
reduces the long-range, but not the short-range, signaling capacity of these
morphogens and alters their trafficking behavior
(Panáková et al.,
2005).
How does lipoprotein association affect the function of morphogens? One
obvious possibility is that they act as vehicles for the spread of
lipid-linked morphogens, whose membrane affinity might otherwise prevent their
long-range dispersal. This model implies that endocytic receptors or other
surface binding sites for lipoproteins might influence the spread or
downregulation of lipoprotein/morphogen signals. It seems unlikely that the
LDL receptor itself influences the spread of morphogens because LDL
receptor-deficient organisms develop normally, without alterations in Hh or Wg
signaling. However, the possibility remains that other LRPs influence
morphogen trafficking. The Drosophila LRP5/6 homolog Arrow is
essential for Wg signaling (reviewed by He
et al., 2004). Although LRP5/6 is only distantly related to other
LRPs (see Fig. 1 for details),
evidence exists that it might actually bind to lipoproteins in mice
(Kim et al., 1998;
Magoori et al., 2003).
Although Arrow is not required for Wg internalization, it does appear to
influence the rate of Wg degradation after endocytosis
(Marois et al., 2006).
Lipoprotein receptors LRP1, LRP2 and LRP4 also have important roles in
development, but whether they affect the spread of morphogens has not been
specifically examined. However, LRP2 appears to be able to internalize SHH in
cultured rat yolk sac cells (McCarthy et
al., 2002). Finally, heparan sulfate proteoglycans can also bind
and internalize lipoproteins independently of LRPs
(MacArthur et al., 2007;
Wilsie et al., 2006) and
clearly have important and ubiquitous functions in regulating the spread of
Wnt and Hh family proteins (Blair,
2005; Hacker et al.,
2005; Nybakken and Perrimon,
2002b). It will be interesting to examine whether they do so by
interacting with lipoproteins.
|
).
Although speculative, clustering might be affected by simultaneous binding of
Frizzled to Wnt and Arrow to apolipoproteins in the morphogen-modified
lipoprotein. Similarly, LRP1 also has been suggested to form competing
complexes with Frizzled in cultured cells, inhibiting Wnt signaling
(Zilberberg et al., 2004).
This observation supports the intriguing possibility that multiple
interactions between Wg, Frizzled, LRPs and lipoproteins could regulate Wg
signaling pathways during development (Fig.
4A).
In addition to a role in Wnt signaling, a possible role for LRPs in Hh
signaling has also been suggested based on the recent observation that the
Hh-dependent activation of cyclin D transcription in mouse granule neuron
precursor cells can be blocked by the receptor-associated protein (RAP; also
known as LRPAP1 - Mouse Genome Informatics) - a factor that competitively
inhibits ligand binding to LRPs (Vaillant
et al., 2007). It will be interesting to determine whether a
lipoprotein-Hh association might promote such interactions
(Fig. 4B). The above study also
showed that the LRP ligand PN-1 (also known as SERPINE2 - Mouse Genome
Informatics) specifically interferes with Hh signaling in these cells and
causes Hh gain-of-function phenotypes when mutated in mice
(Vaillant et al., 2007). One
possible explanation for these data is that LRP1 has a positive role in Hh
signaling and that PN-1 competes with Hh for binding to this receptor.
Lipoproteins may deliver sterols to regulate the hedgehog pathway
In addition to modulating Wnt and Hh signal transduction across the plasma
membrane, endocytic uptake of morphogen-modified lipoproteins may also combine
morphogen signaling with cellular delivery of regulatory sterols
(Fig. 4B). Recently, studies on
the involvement of cholesterol derivatives in Hh regulation have indicated
such an exciting possibility. The Hh family controls patterning and
proliferation in a wide diversity of tissues and phyla - the basic components
of this signaling pathway are depicted in
Fig. 5A. Hh signals by binding
to and inhibiting Patched (PTC), a twelve-transmembrane-domain protein that is
a member of the resistance nodulation division (RND) superfamily of
transmembrane transporters (Tseng et al.,
1999). In the absence of Hh, PTC is thought to pump a small
molecule across the bilayer to repress the activity of Smoothened (SMO) - a
seven-pass-transmembrane receptor (Chen et
al., 2002; Taipale et al.,
2002). When repression is relieved, activated SMO induces the
transcription of Hh target genes by regulating the stability, nuclear
translocation and activation of Cubitus interruptus, a Gli family
transcription factor (Fig. 5A)
(reviewed by Aza-Blanc and Kornberg,
1999; Kalderon,
2005; Lum and Beachy,
2004; Nybakken and Perrimon,
2002a).
Links between Hh signaling and sterol metabolism have been identified at
almost every level of the Hh pathway. Indeed, Hh family proteins are
themselves covalently modified by both cholesterol
(Porter et al., 1996;
Wendler et al., 2006) and
palmitate (Pepinsky et al.,
1998) in a way that is essential for their function. The Hh
receptor, PTC, contains a sterol-sensing domain, and its closest relative
within the RND family is Niemann-Pick type C1 (NPC1) - the protein required to
mobilize sterols from endocytic compartments
(Fig. 2A)
(Ikonen and Holtta-Vuori,
2004; Mukherjee and Maxfield,
2004). Hh secretion requires Dispatched, another member of the RND
transporter family with a sterol-sensing domain
(Burke et al., 1999). Finally,
Hh lipid modifications allow association not only with cell membranes, but
also with lipoprotein particles - which are, of course, full of sterols
(Panáková et al.,
2005). Despite this plethora of clues, the exact nature of the
relationship between sterols and Hh signaling has remained murky. Recent
findings showing how specific sterol derivatives influence Hh pathway activity
have begun to provide insight into this relationship.
|
; Cooper et al.,
1998). It has been hypothesized that PTC might pump a structurally
related endogenous molecule across the membrane to repress SMO in vivo.
Bijlsma and colleagues now demonstrate that supernatants from PTC-expressing
cells contain such a SMO inhibitor. Results from experiments using cells that
are mutant for different enzymes in the cholesterol biosynthesis pathway
indicate that this inhibitor is likely to be produced from
7-dehydrocholesterol, the precursor of vitamin D3
(Bijlsma et al., 2006).
Interestingly, PTC expression increases the efflux of this class of molecules
into the culture medium, where it associates with LDL
(Fig. 5C). Bijlsma and
colleagues show that vitamin D3 competes with cyclopamine for
binding to SMO-expressing yeast cells and is a potent inhibitor when added to
a SMO-transfected mouse fibroblast cell lines. However, whereas the inhibitor
produced by their cell line relies on endogenous sterol biosynthesis, in vivo
vitamin D3 can be derived only by UV irradiation of
7-dehydrocholesterol in the skin or by nutritional uptake
(Dusso et al., 2005) and would
almost certainly have to be taken up from the extracellular fluids into Hh
target cells. Endogenous vitamin D3 that is produced in the skin is
transported by DBP through the circulatory system. By contrast, vitamin
D3 absorbed from the diet is delivered by lipoprotein particles
(Haddad et al., 1993). Should
vitamin D3 turn out to be the relevant regulator of SMO in vivo, it
would suggest possible novel functions for both lipoproteins and their
receptors in the regulation of the Hh pathway
(Fig. 5C). LRP2, the receptor
for uptake of vitamin D3 metabolites complexed with DBP, might be
of particular relevance (Fig.
5C).
Oxygenated forms of cholesterol (oxysterols) are another group of
cholesterol derivatives that have been identified as regulators of the Hh
pathway. They arise from cholesterol by auto-oxidation or by specific
microsomal or mitochondrial oxidation processes. Previously, oxysterols had
been shown to regulate cholesterol biosynthetic pathways by interacting with
nuclear hormone receptors in the adult organism. Now, oxysterols have also
been uncovered as positive regulators of the Hh pathway in mouse
medulloblastoma cell lines and in pluripotent mesenchymal cells
(Corcoran and Scott, 2006;
Dwyer et al., 2007).
Medulloblastoma arises frequently in mice heterozygous for patched 1
(Ptch1), and continued proliferation of this tumor depends on
activation of the Hh pathway (Berman et
al., 2002). It has previously been shown that sterols are required
for Hh pathway activation at the level of SMO
(Cooper et al., 2003).
Corcoran and colleagues confirm that both proliferation and Hh target gene
activation in medulloblastoma cells derived from Ptch1-/-;
p53-/- (Trp53 - Mouse Genome Informatics) mice depend
on their ability to synthesize cholesterol. They further show that, when
cholesterol synthesis is blocked, target gene activation and proliferation can
be restored by the addition of specific oxysterols derived from cholesterol.
Their data suggest that the requirement for sterols in SMO activation reflects
a signaling function for an oxysterol derivative
(Fig. 5B).
Oxysterols have been known for some time to promote the differentiation of
bone, rather than adipose tissue, from pluripotent mesenchymal cells
(Kha et al., 2004). Dwyer and
colleagues now show that oxysterols exert their function in these cells by
activating the Hh pathway at or above the level of SMO
(Dwyer et al., 2007;
Kha et al., 2004). Oxysterols
do not further activate the pathway in Ptch1 homozygous mutant mouse
fibroblasts, in which SMO is constitutively active owing to the absence of
PTCH1-mediated repression. This fact, along with the failure of oxysterols to
compete with cyclopamine for binding to SMO, led these investigators to
conclude that oxysterols do not act directly on SMO
(Fig. 5B). Instead, they
suggest that oxysterols modulate the pump activity of PTC and note that sterol
binding to other sterol-sensing domain proteins, such as sterol regulatory
element-binding protein cleavage activating proteins (SCAP), has an important
regulatory function.
Although it is primarily endogenous synthesis that generates the
stimulatory sterol derivative in these systems, it is interesting to consider
whether exogenous sources could also contribute in vivo. Hh pathway elements
are strictly conserved in Drosophila, which, like all insects, do not
have the capacity for de novo cholesterol biosynthesis and are dependent on
nutritional sources of this sterol
(Clayton, 1964;
Svoboda, 1999). If the
function of oxysterols or vitamin D3 is conserved in this organism,
then lipoproteins and their receptors might have important roles to play in
delivering these components. Oxidized lipoproteins might provide an external
source of oxysterol.
Conclusion
Starting with the simple concept that lipoproteins provide lipids with structural or nutritional function, our perspective of embryonic lipoprotein metabolism has become significantly more sophisticated, but also much more complex. We now know that lipoproteins act as scaffolds for the assembly of signaling factors and that lipoprotein receptors act as co-receptors in embryonic patterning pathways; cholesterol metabolites represent inducers or repressors of morphogen action in these scenarios.
While an understanding of the molecular concepts of lipid transport and uptake unfolds, there is yet another problem to be tackled concerning the intracellular fate of sterols. What mechanisms determine whether internalized cholesterol is converted into steroid hormones that are destined for secretion, or whether it is turned into intracellular hormones that activate nuclear hormone receptors, or perhaps even converted into regulators of SMO? As in the circulatory fluids, the transport of sterols in the cytoplasm is facilitated by proteins. Thus, a number of transporters have been identified that traffic sterols in and out of organelles and across membrane bilayers. These pumps include members of the ATP-binding cassette (ABC) superfamily as well as NPC1 and related factors (e.g. NPC2, NPC1-like 1). In addition, cytoplasmic carriers that solubilize cholesterol and its metabolites in the aqueous milieu of the cell have been uncovered, which include lipid-transfer proteins (e.g. START-domain-containing proteins) and oxysterol-binding proteins. The elucidation of the mechanisms that link extracellular transport and receptor-mediated uptake of sterols with distinct intracellular trafficking routes (and hence cellular functions) will be one of the future challenges in the field of embryonic lipoprotein metabolism.
ACKNOWLEDGMENTS
The authors thank members of their laboratories for helpful discussions.
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