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Lutz
W. Weber, 554 Mariner Point Drive, Clinton, TN 37716, USA
Meinrad Boll, Andreas Stampfl, Institute for Toxicology, GSF
- National Research Center for Environment and Health, Munich,
D-85758 Neuherberg, Germany
Correspondence to: Lutz W. Weber, Institute of Toxicology,
GSF - National Research Center for Environment and Health, Munich,
D-85758 Neuherberg, Germany. stampfl@gsf.de
Telephone: +49-89-3187-2625
Fax: +49-89-3187-3449
Received: 2003-10-15
Accepted: 2004-04-13
Abstract
The molecular mechanism of how hepatocytes maintain cholesterol
homeostasis has become much more transparent with the discovery of
sterol regulatory element binding proteins (SREBPs) in recent years.
These membrane proteins are members of the basic helix-loop-helix-leucine
zipper (bHLH-Zip) family of transcription factors. They activate the
expression of at least 30 genes involved in the synthesis of
cholesterol and lipids. SREBPs are synthesized as precursor proteins
in the endoplasmic reticulum (ER), where they form a complex with
another protein, SREBP cleavage activating protein (SCAP).The SCAP
molecule contains a sterol sensory domain. In the presence of high
cellular sterol concentrations SCAP confines SREBP to the ER. With
low cellular concentrations, SCAP escorts SREBP to activation in the
Golgi. There, SREBP undergoes two proteolytic cleavage steps to
release the mature, biologically active transcription factor,
nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds
to sterol response elements (SRE) in the promoter/enhancer regions
of target genes. Additional transcription factors are required to
activate transcription of these genes. Three different SREBPs are
known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced
from a single gene by alternate splicing. SREBP-2 is encoded by a
different gene and does not display any isoforms. It appears that
SREBPs alone, in the sequence described above, can exert complete
control over cholesterol synthesis, whereas many additional factors
(hormones, cytokines, etc.) are required for complete control of
lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is
expected to prove highly beneficial in the management of
cholesterol-related disease.
Weber LW, Boll M,
Stampfl A. Maintaining cholesterol homeostasis: Sterol regulatory
element-binding proteins. World J Gastroenterol 2004; 10(21): 3081-3087
http://www.wjgnet.com/1007-9327/10/3081.asp
INTRODUCTION
The view of cholesterol as a nasty substance which clogs
arteries and causes heart disease is wide-spread, but it does not do
the molecule justice. Not only is it a vital component of cell
membranes without which the cell cannot function, but it is also the
precursor to all steroid hormones, bile acids, and oxysterols, which
by themselves are important regulatory molecules in many metabolic
pathways.
Cholesterol and fatty
acids as building blocks of cell membranes are synthesized via
regulated pathways. All cells must control
these pathways in order to maintain levels within
physiological boundaries. Excessive amounts of cholesterol in cells
can destroy membrane function, precipitate as crystals which will
kill the cell or result in atherosclerotic damage if spread to blood[1].
However, the original view of random distribution of cholesterol and
lipids in the cell membrane no longer holds: not only differs the
lipid composition of the outer leaflet of the plasma membrane from
the inner one, but the distribution of lipids and cholesterol in the
outer leaflet is organized into domains, with so-called rafts[2]
and caveolae[3] being rich in cholesterol and
sphingomyelin. These structures play intricate roles in cholesterol
trafficking to maintain cellular homeostasis, and they are also
components of the cellular signalling system.
The membranes of endoplasmic reticulum (ER) and Golgi, on the
other hand, contain comparatively little cholesterol, a factor
important in its own homeostasis, and one objective of this
overview.
The understanding of
cholesterol regulation has come a long way from the initial
recognition of cholesterol feedback inhibition of its rate-limiting
synthetic enzyme, 3-hydroxy-3- methylglutaryl coenzyme A (HMGCoA)
reductase, through the role of lipoproteins in maintaining plasma
cholesterol levels, to the recent discoveries of regulation of
cholesterol synthesis via sterol-sensitive response elements (SREs),
and degradation via liver X receptor (LXR) - or bile acid receptor
(BAR) -regulated pathways.
Lipid homeostasis via
SREs in animal cells is achieved by a family of transcription
factors called SRE-binding proteins (SREBPs). SREBPs activate
directly the expression of some 30-plus genes participating in the
metabolism mostly of lipids, but also glucose. Activation of these
originally membrane-bound transcription factors involves a
proteolytic cascade through which the SREBP molecule is released
from the membrane and obtains its mature form as a transcription
factor. The active SREBP enters the nucleus and binds to those
special DNA sequences, the SREs, in the promoter regions of many
different genes.
In the health arena,
SREBPs stand at a crucial point: they regulate expression of the LDL
receptor, the molecule which enables the hepatocytes to remove
cholesterol contained in LDL particles from the bloodstream. High
(dietary) cholesterol prevents maturation of SREBPs and not only
cuts off cholesterol synthesis, but also LDL receptor synthesis,
resulting in high blood cholesterol and the imminent danger of
atherosclerotic plaque formation. At this point in time the
so-called statins, drugs which block HMGCoA reductase, another
target of SREBP-mediated gene expression, are the most effective way
to interrupt this vicious circle[4].
This brief overview is
concerned with the SREBP-mediated control of cholesterol and lipid
synthesis. Lipid synthesis is subject to many other regulatory
influences which cannot be addressed here, nor can the degradation
of cholesterol via hormone or bile acid synthesis be covered, which
again commands its own set of regulatory substances. The focus of
this minireview is to present the latest data on the SREBP-induced
mechanism. Recent in-depth reviews have been available[5-9].
Figure
1(PDF)
Feedforward and feedback effects of oxysterols FXR =
farnesoid×receptor;
LRH-1 = liver receptor homologue-1; LXR = liver×receptor;
SF-1 = steroidogenic factor-1; SREBP = sterol responsive element
binding protein.
OXYSTEROLS AS NEGATIVE AND POSITIVE REGULATORY MOLECULES
Cholesterol is not the only sterol inside the cell to act as a
regulatory substance, many of its hydroxylated derivatives, the
oxysterols, share these important functions. Oxysterols exert a
feed-back effect and down-regulate cholesterol synthesis, to be
detailed in the following sections of this overview, but they also
up-regulate their own metabolism and elimination via a feed-forward
effect which will be briefly described in this section.
Cholesterol
directly affects two enzymes which are vital in its own removal. It
activates acyl-CoA: cholesterol acyl transferase (ACAT), the enzyme
required to synthesize cholesteryl esters, its major storage form,
and it also activates cholesterol 7a-hydroxylase
(CYP7A1), the initial and rate-limiting enzyme of bile acid
synthesis, the leading pathway of cholesterol elimination[10].
The side
chain-hydroxylated 27-hydroxycholesterol is presumed to function in
cholesterol homeostasis by sustaining HDL-mediated reverse
cholesterol transport, the process by which cholesterol is brought
back to the liver from peripheral tissues[11]. The most
important action of oxysterols, however, is to serve as ligands for
nuclear orphan receptors. This family of proteins has been
recognized as nuclear hormone receptors based on their molecular
properties, but since ligands were initially not known, they were
named orphan receptors. Most important among these is liver X
receptor (LXR), which controls expression of CYP7A1[12]
as the rate-limiting step of bile acid synthesis[13,14],
reverse cholesterol transport[15], trafficking of
cholesteryl esters, and aids in lipid metabolism[16] and
the intestinal absorption of cholesterol. This receptor displays
specific requirements for the position of additional hydroxy group
(s) on the cholesterol molecule, the most potent ligands being 20
(S) -OH-, 22 (R) -OH-, 20, 22-di-OH-, and 24-OH-cholesterol[17,18].
An overview of oxysterol actions is shown in Figure 1.
Furthermore, oxysterols
are ligands for steroidogenic factor-1 (SF-1) and liver
receptor-homologue 1 (LRH-1), in which they regulate steroid hormone
synthesis and sexual differentiation during prenatal development.
SF-1 is limited to steroidogenic tissues, whereas LRH-1 occurs in
liver and other tissues derived from the gut endoderm[7].
Oxysterols also play a role in meiosis[19]. Finally,
these bile acids activate the farnesol X receptor (FXR) /retinoid X
receptor (RXR)/receptor-interacting protein 14 (Rip14) system, FXR
is also known as bile acid receptor (BAR).
Binding of bile acids to FXR inhibits bile acids synthesis.
SREBPS, MEMBRANE-DERIVED
TRANSCRIPTION FACTORS
SREBPs belong to the large family of basic helix-loop-helix-leucine
zipper (bHLH-Zip) transcription factors. Three members of the SREBP
family, SREBPs-1a, -1c, and -2, have been identified[20,21].
They are synthesized as inactive precursors.
Isoforms -1a and -1c are produced from a single gene on human
chromosome 17p11.2 by use of alternate promoters and splicing,
resulting in different forms of exon-1[21-23]. SREBP-2 is
encoded by a separate gene on human chromosome 22q13[20,24].
It has about 50% sequence identity with SREBP-1. Adipocyte
determination differentiation factor (ADD)-1, a transcription factor
which binds to E-boxes and promotes adipocyte differentiation in
rats[25] is the homologue of
human SREBP-1c[23].
Each nascent SREBP
protein has a molecular size of about 125 ku and consists of about 1
150 amino acids (aa) in 3 functional domains. The first,
NH2-terminal domain of SREBP contains the bHLH-Zip and an acidic
domain, located at the very NH2 terminus. The acidic
domain has to bind a transcription coactivator for function, it is
shorter in SREBP-1c than in SREBP-1a, making SREBP-1c a weaker
transcription activator[26]. The acidic domain is
essential for function. When removed, the bHLH-Zip portion of SREBP
still binds to DNA, but no longer activates transcription, thus
acting as an inhibitor[27].
A djacent to the acidic
DNA-binding domain is a variable area rich in serine, proline,
glutamine, and glycine. Next follows the bHLH-Zip sequence, whose
basic region mediates DNA binding. The rest of the bHLH-Zip motif
imparts the ability to dimerize. Other bHLH-Zips tend to homo-dimerize,
whereas SREBP needs other transcription factors such as SP-1 or NF-Y
for full function. The remainder of the SREBP molecule has no
analogy with other bHLH-Zip transcription factors[5].
SREBPs are embedded in
membranes of the endoplasmic reticulum (ER) and the nuclear
envelope, forming what has been called a hairpin shape[28,29].
The NH2-terminal portion of the SREBP molecule through
the bHLH-Zip region protrudes into the cytosol. The following
central portion of SREBP, the membrane anchoring region, is about 90
aa in length. It consists of two hydrophobic, membrane-spanning
segments separated by a hydrophilic loop which extends into the
lumen of the ER. The
COOH terminal segment of about 590 aa again extends into the cytosol
and serves as the regulatory domain for transformation into the
mature, a transcriptionally active form also known as nuclear SREBP
(nSREBP). Neither the membrane-spanning, nor the regulatory regions,
are found in other bHLH-Zip transcription factors.
The NH2-terminal
domain of SREBP binds to a sterol binding element (SRE) which must
contain a direct, or tandem, repeat of the recognition sequence[30].
This is another evident difference to bHLH-Zip transcription
factors, which will bind only to palindromic (i.e., tail-to-tail
connected) repeats. SREBPs display no in vivo activity with
palindromic sequences[5,19].
SREBP CLEAVAGE ACTIVATION
PROTEIN (SCAP), AN ESCORT AND STEROL SENSOR PROTEIN
SREBPs attain biological activity only after being transferred
to the membrane of the Golgi complex, where they are cleaved at the
lumenal loop and the NH2-end is released from the
membrane. They are confined to the membranes of the ER unless they
are paired up with another protein which serves two functions: to
sense the levels of sterols in the cell, and in response to low
sterol levels, to escort SREBP to its place of activation.
This is achieved by SREBP cleavage activating protein (SCAP),
a protein originally cloned from a mutant cell line of Chinese
hamster ovary cells which will not suppress SREBP cleavage even with
very high sterol levels[31]. The mutation affects one
specific codon, 443, where a C (ytosine) to G (uanine) transition on
the DNA side replaces an aspartic acid by an asparagine in the amino
acid sequence, rendering SCAP unresponsive to sterols[32].
SCAP has 1 276 amino
acids[31] in two domains[33]: a
membrane-spanning NH2 terminal domain of 730 aa, and a
COOH terminal domain of 546 aa, which extends into the cytosol.
The NH2-terminus contains eight hydrophobic
sequences separated by short hydrophilic loops[31], the
hydrophobic sequences are thought to span the membrane with the
hydrophilic loops protruding at either side. SCAP shares this
feature with HMGCoA reductase[34,35]. The
membrane-spanning stretches comprise the sterol-sensing area,
whereas the COOH-terminus contains all of the remaining biological
activity[31]. The COOH-terminus is organized in five
repeat sequences characteristic of the WD family. Wherever this
sequence occurs, it mediates protein-protein interactions[36].
Newly synthesized SREBP
forms a tight complex with the WD repeat domains of SCAP[37],
but in the presence of oxysterols this complex is confined to the
ER, establishing a feedback loop to control cholesterol synthesis.
With oxysterol depletion, the SCAP/SREBP complex appears in vesicles
budding from ER membranes[38] and translocates to another
subcellular compartment, the Golgi[39-43]. Transfer of
SREBP and proteolytic cleavage to release nSREBP cannot occur unless
this complex has formed[42]. Oxysterols induce a change
of the conformation of SCAP, and an additional protein has been
postulated to retain SCAP in the ER once in its sterol-induced
conformation[44]. Not
only cholesterol, but also several other oxysterols display full
activity in suppressing SCAP translocation into vesicles, but it has
been suggested that cholesterol alone exerts the effect, while high
levels of oxysterols simply force translocation of cholesterol from
the plasma membrane to the ER[44]. Complete understanding
could be of immense benefit in the management of hyperlipidemias.
SREBP ACTIVATION VIA TWO-STEP
PROTEOLYTIC CLEAVAGE
The SREBP/SCAP-containing vesicles from the ER also contain a
membrane-anchored serine protease of the subtilisin family, Site-1
protease (S1P), in an inactive form which becomes activated only
during its transport to the Golgi[45]. The SREBP/SCAP
complex and S1P now incorporate into the Golgi membrane. As the next
step, the activated S1P attaches to the SCAP/SREBP complex and cuts
the SREBP molecule right in the middle of its lumenal hydrophilic
loop[29]. When active S1P is inserted into the ER, it
will cleave SREBP without a need for SCAP[43].
To release active SREBP,
another enzyme is required, Site-2 protease (S2P, a trans-membrane
zinc metalloprotease). The cellular location of this enzyme is as
yet unclear, but likely resides in the Golgi. S2P cuts the still
membrane-anchored SREBP in a rather unusual place, viz., three amino
acids into the membrane-spanning portion on the cytoplasmic
side[46,47]. This process is known to regulate intra-membrane
proteolysis (Rip)[48], and typically produces proteins
which are transcriptionally active and participate in the control of
various cellular processes[6]. S2P action is not directly
affected by cellular oxysterol levels, since this enzyme cannot act
unless S1P has separated the bHLH-Zip portion of SREBP from the
regulatory COOH terminus[49]. S2P action results in the release of a
mature, 68 kDa nSREBP, consisting of the bHLH-zipper domain with the
first three membrane-spanning amino acids attached, which now can
migrate to the nucleus and bind to a sterol-responsive element (SRE).
SCAP is recycled back to the ER to chaperone another 125 kDa SREBP
molecule to the Golgi[50], whereas the 68 kDa SREBP is
degraded. Interestingly, the nuclear action of nSREBP induces new
SREBP mRNA synthesis by way of SREs located in the promoter regions
of their own genes[51]. A synopsis is shown in Figure 2.
The
process of SREBP cleavage and activation thus comprises 4 components
which, upon mutation, can result in loss of oxysterol-sensitive
regulation of cholesterol homeostasis.
As a matter of fact, much of the knowledge of the SREBP
regulatory system stems from experimentally mutated cell lines and
subsequent selection for oxysterol resistance or cholesterol
auxotrophy[8]. Oxysterol
resistance has aided in cloning the genes for SREBP and SCAP,
respectively. One type, class 1 mutation, produces an NH2-terminal
bHLH-Zip portion of SREBP which is truncated even before the S2P
cleavage site[52,53]. This molecule is therefore not
membrane bound and can access the nucleus immediately after its
synthesis, turning on the complete SREBP gene battery regardless of
cellular oxysterol levels. Class 2 mutants contain a mutated SCAP
molecule[54] which holds the SREBP/SCAP/S1P complex in a
permanently active configuration, no matter how high the oxysterol
level in the cell, resulting in permanent release of nSREBP with
concomitant overproduction of cholesterol[31].
Cholesterol auxotrophy
has been used as a selection criterion to clone the genes for S1P
and S2P. With S1P[55], S2P[41,46,56] or SCAP[57]
rendered non-functional, cells become dependent on exogenous
cholesterol because they cannot produce the enzymes necessary for
its biosynthesis.
It is interesting to know
that the proteolytic activation of SREBP-1 and SREBP-2,
respectively, can be regulated individually. In rodents, treatment
with cholesterol suppressing drugs (statins) or with
cholesterol-sequestering agents results in up-regulation and
increased activation of SREBP-2 while reducing activation of SREBP-1[58].
Another interesting feature is that polyunsaturated fatty acids
inhibit the proteolytic activation of SREBP-1, but contrary to the
action of oxysterols, they have no effect on SREBP-2 maturation[59].
In addition, glucose metabolites such as glucose-6-phosphate may
serve to accelerate maturation of SREBP-1c only[60], but
mechanistic details have not been elucidated.
Figure 2(PDF)
Maturation
of SREBPs -NH2
= amino-terminal ends of SREBP or SCAP. S1P = Site-1 protease
(crossed-out = inactive); S2P = Site-2 protease. SRE =
sterol-responsive element; nSREBP = nuclear SREBP. Arrangement of
the additional transcription factors NF-Y,
Sp1, CREB, ARC, CBP, TBP, and DRIC (see text) is tentative as their
requirements are not exactly known.
GENE ACTIVATION BY SREBPs, TARGET GENES
Immediately after the second cleavage of the SREBPs the now
mature protein enters the nucleus where it binds to SREs in the
promoters of the target genes and activates transcription. The SRE
nucleotide sequence displays considerable variation among the
promoters of the many genes activated by an SRE, a commonly found
sequence is represented by 5'-nTCACnCCA
C n-3' (cf.[6]). However, SREBP alone cannot activate
transcription, but must act co-ordinately with additional
transcription factors to obtain full activation of target genes.
Transcription factors
known to activate SREs in conjunction with SREBP are Sp1, nuclear
factor (NF)-Y, and cAMP response element binding protein (CREB)[10,61-64].
NF-Y interacts directly with SREBP[62], and Sp1 can
stabilize the complex[61]. It appears that the promoters
of different SRE-activated genes respond to different combinations
of these transcription factors. Once a stable complex has formed in
a promoter region, additional factors such as CREB binding protein (CBP)[65,66],
activated recruited cofactor (ARC)[67], vitamin D
receptor interacting protein (DRIC)[67], or TATA
box-binding protein (TBP)-associated factors may be recruited to
initiate transcription. Histone
acetylation is also required for full transcriptional activity[68].
Such complexes have been shown to exist with SREBP-1a and -2, but
not with SREBP-1c. This may explain its rather weak potency to
activate the SRE gene battery.
SREBP-activated
genes predominantly belong to lipid metabolism pathways, viz,
cholesterogenesis, fatty acid synthesis, lipogenesis, triglyceride
and phospholipid synthesis, but also glucose metabolism. Yet, the
three SREBPs do not activate identical gene batteries. Using
transgenic mice over-expressing just one type of nSREBP it has been
discovered that SREBPs-1a and -1c actions favour fatty acid
synthesis, whereas SREBP-2 action favours cholesterol synthesis[5,69-71],
but in vitro both SREBPs-1a and -2 can trigger expression of the
complete set of enzymes required for cholesterol synthesis with
similar potency[72]. While SREBPs-1a and -2 predominate
in cultured cells, intact liver and most other tissues primarily
express SREBP-1c and -2[9]. An overview of SREBP pathways
is given in Figure 3.
Figure
3(PDF)
Metabolic pathways regulated by SREBPs G-6-P =
glucose-6-phosphate; 6-PG = 6-phosphogluconate; Rib-5-P =
ribulose-5-phosphate; PEP = phosphoenol pyruvate; CoA = coenzyme A;
HMGCoA = 3-hydroxy-3-methylglutaryl coenzyme A. SREBP-1c and SREBP-2
activate genes for the generation of NADPH (ATP citrate lyase, malic
enzyme, G-6-P dehydrogenase, 6-PG dehydrogenase) required in various
steps of lipid synthesis.
SREBP-2
over-expression induces all 12 enzymes of the cholesterol
biosynthetic pathway[72], most notably the mRNA for
HMGCoA reductase, which may increase as many as 75-fold[73].
Overall cholesterol synthesis in such animals is up 28-fold, whereas
fatty acid synthesis is increased only 4-fold. In contrast,
expression of enzymes does not involve cholesterol synthesis but is
related to cholesterol metabolism. Cholesterol 7a-hydroxylase
(rate-limiting enzyme for bile acid synthesis) and
acyl-CoA:cholesterol acyltransferase (ACAT, catalyses cholesterol
ester formation), are not activated[72].
SREBP-1a appears to be
constitutively expressed in most tissues, with as yet no known
factor to stimulate its low expression[26].
Over-expression in adult rats also resulted in over-stimulation of
lipid synthesis, but in this case fatty acid synthesis was increased
26-fold, and cholesterol synthesis 5-fold. Since SREBP-1a and -1c
(see below) also induce enzymes for fatty acid elongation and
desaturation[73,74], SREBP-1a over-expression resulted in
elevated hepatic levels of oleate[75].
SREBP-1c is predominantly
involved in the regulation of adipogenesis and also in the
regulation of insulin-responsive genes which control lipogenesis and
glucose metabolism[76,77], but in vitro it does not
stimulate cholesterol synthesis[75]. SREBP-1c mRNA
synthesis responds to nutritional changes in parallel to insulin
levels[78]. Insulin heightens the expression of SREBP-1c
and its battery of genes involved in the synthesis of saturated and
unsaturated fatty acids[75,79] as well as glucose
metabolism genes[77,78]. The effect is opposed by
glucagon and cyclic AMP. In short, available experimental data
indicate that SREBP-1c mediates all effects of insulin on
lipogenesis. In response to nutritional stimuli SREBP-1c also
triggers expression of genes of enzymes required for fatty acid
elongation[74], and of glycerol 3-phosphate
acyltransferase required for triglyceride and phospholipid synthesis[6].
Last but not least SREBPs activate 3 genes necessary for the
generation of NADPH, which is needed in fatty acid and cholesterol
synthesis.
The
promoter of the SREBP-1c gene contains response elements for
insulin, glucagon, as well as liver X-activated receptors (LXR)a
and
LXRb,
the latter is activated by sterols[17,43]. This
regulatory pathway, among others, results in increased synthesis of
oleate[75], the major fatty acid used for cholesterol
esterification, to ensure its removal from the liver.
KNOCK-OUT
ANIMALS AND HEALTH IMPLICATIONS OF SREBPS
Knock-out mice which lack all SREBPs, or S1P to activate them,
die at an early stage of embryonic development[80,81].
Specific knock-out of SREBP-2 also results in embryonic lethality.
Deletion of SREBP-1a allows some foetuses to survive, whereas lack
of SREBP-1c appears to be of no consequence. The survivors are found
to compensate by higher SREBP-2 levels, and consequently, these
animals have elevated hepatic cholesterol, but lower fatty acid
levels[9].
In order to study SREBP
knock-outs in adulthood, a gene manipulation was used in Brown and
Goldstein's laboratory which allows to turn specific genes off at
will by stimulating interferon production. Disruption of the SCAP or
S1P gene, respectively, almost abolished nSREBPs-1 and -2 in liver
and diminished expression of all target genes of cholesterol and
fatty acid synthesis. The result was a reduction in cholesterol and
fatty acid levels in livers by 70-80%[9].
The SREBP-related links
between fatty acid and glucose metabolism draw immediate attention
to the wide-spread disease, diabetes. It would appear that the fatty
liver frequently observed in insulin-resistant diabetics is a result
of high SREBP-1c levels caused by high insulin levels. Leptin, the
organism's response to fat accumulation in adipocytes, opposes
SREBP-1c action[82], and consequently can heal the
derailment of fat metabolism in diabetic animals[83].
One of the genes
activated by nSREBP-1c is that for the hepatic LDL receptor, an
effect clearly targeting at maintaining plasma lipid homeostasis. At
first sight this would appear beneficial for arteriosclerosis since
it should reduce elevated LDL-cholesterol levels in blood. However,
since nSREBP-1c also induces lipogenesis, its effect is ambiguous,
and other factors will decide whether the net result fights
arteriosclerosis, or rather exacerbates it[7]. It is at
this point where the HMGCoA reductase inhibitors or statins work,
but they are effective only in one third of cases[84].
It must be understood
that fatty acid synthesis is not only subject to SREBP regulation,
but a host of other factors, whereas cholesterol synthesis appears
to be exclusively controlled by SREPBs. Additional unknowns are the
exact regulation of system by which HDL via the scavenger receptor
B-1 mediates efflux of cholesterol from the liver, and the
ATP-binding cassette-1 (ABC-1) system which mediates transfer of
cholesterol to HDL[84]. Profound knowledge of these
pathways will open a perspective beyond the statin drugs to
specifically lower cholesterol levels in disease conditions.
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