Cholesterol and Other Steroids

S Sitaula, The Scripps Research Institute, Jupiter, FL, USA

TP Burris, Saint Louis University School of Medicine, St. Louis, MO, USA
r 2016 Elsevier Inc. All rights reserved.

Introduction Structure

Cholesterol is a major component of cell membranes and The structure of cholesterol was elucidated in the twentieth
a precursor to many important biological molecules. Since century by the work of many scientists including Nobel
the discovery of cholesterol from gallstones in the eighteenth Laureates Otto Diels, Robert Robinson, Heinrich Wieland,
century, it has been a molecule of great interest and has Adolf Windaus, and Leopold Ruzicka (Brock, 2000). Choles-
been studied extensively. As a result, 13 Nobel Prizes have terol belongs to the family of polycyclic compounds known as
been awarded to researchers who contributed to the study sterols. This 27-carbon structure has rigid planar rings and a
of cholesterol, its chemistry, biochemistry, physiological flexible tail (Figure 1). Cholesterol is comprised of four
role, and its clinical significance. Cholesterol metabolism hydrocarbon rings, a hydroxyl group attached to C3 and an
has complex regulatory mechanisms and new functions eight-carbon tail. The four planar rings contribute to the
for this molecule in cell biology and disease processes are hydrophobicity of the molecule while the hydroxyl group is
being uncovered even hundreds of years after its initial hydrophilic, making cholesterol amphipathic (Bloch, 1983).
discovery. Although cholesterol is slightly polar, it is highly insoluble in
There is considerable evidence demonstrating that choles- water. In the cell membrane cholesterol orients with the
terol is indispensable for normal functioning of a cell. Cho- hydrophobic rings facing the fatty acid chain of the phos-
lesterol is important for many biological processes and its pholipid and the polar hydroxyl group facing the aqueous
accumulation or depletion can be detrimental to the body as layer. While the hydroxyl group confers polarity to the mol-
evidenced by multiple disorders identified in animal models ecule allowing it to form a part of the cell membrane, it is also
and in humans with defective cholesterol homeostasis. Due to important as a site for esterification of cholesterol. These
the fine balance that exists between its essential role in normal chemical properties allow cholesterol to form an integral part
biological function and its role in disease, complex regulatory of the cell membrane and perform its functions effectively, but
mechanisms that strictly monitor and regulate the synthesis, interestingly, the same properties make it toxic to cells in
uptake, transport, and elimination of cholesterol have evolved. free form.
This regulation is achieved by feedback regulatory mechanisms
involving a family of transcriptional factors, cholesterol syn-
thesis enzymes, sterol-sensing proteins, and lipoprotein Cholesteryl Esters
receptors.
Cholesterol has important functions in membrane dy- Most of the cholesterol in humans exists in ester form. Cho-
namics, bile acid synthesis, signal transduction, myelin sheath lesterol converted into cholesteryl ester can be stored and
composition, and steroid hormone formation (Ikonen, 2008; transported more efficiently. Since cholesteryl esters are more
Dowhan et al., 2008). In humans, cholesterol is obtained from hydrophobic than cholesterol, they can be packaged inside the
both the diet and endogenous synthesis. Cholesterol is syn- hydrophobic core of lipoproteins and transported throughout
thesized endogenously by many tissues but the liver is the the body (Ginsburg et al., 1984). Esterification of cholesterol is
predominant site of cholesterol synthesis. Cholesterol syn- required for both delivery of cholesterol to the tissues and for
thesis progresses through a complex pathway that contains removal of cholesterol from peripheral tissues. Cholesterol
many enzymes and is tightly regulated in many steps. The rate esterification is one of the several mechanisms cells use to
of endogenous synthesis of cholesterol depends on a number prevent accumulation of free cholesterol that is toxic to cells
of factors including the amount of cholesterol uptake from (Tabas, 2002). Free cholesterol is esterified in liver and plasma
diet. A feedback mechanism exists that allows the liver to sense by specialized mechanisms. The enzymes lecithin:cholesterol
plasma cholesterol concentrations and regulate cholesterol acyltransferase (LCAT) and acyl-coenzyme A:cholesterol acyl-
biosynthesis in cells. Defects in lipid and cholesterol metab- transferase (ACAT) catalyze the esterification of cholesterol
olism have been associated with conditions such as chole- (Peelman et al., 2000; Chang et al., 1997). Another enzyme
lithiasis, Smith-Lemli-Opitz syndrome (SLOS), Tangier central to cholesterol homeostasis is cholesteryl ester transfer
disease, cancer, neurological conditions, and, most commonly, protein (CETP). CETP plays an important role in transferring
several cardiovascular disorders including atherosclerosis cholesteryl esters and triglycerides between high-density lipo-
(Maxfield and Tabas, 2005; Orth and Bellosta, 2012). A de- protein (HDL) and low-density lipoprotein (LDL) particles
tailed understanding of important players in the cholesterol (Barter, 2003). Lyosomal acid lipase is an enzyme that is re-
synthesis pathway and cholesterol homeostasis processes is quired for breaking down cholesteryl esters into free choles-
fundamental to understanding and treating these cholesterol- terol. Deficiency of this enzyme is associated with disorders
associated disorders. The structure, function, cellular choles- such as Wolman disease and cholesteryl ester storage disease
terol homeostasis, and the role of cholesterol in several characterized by abnormal accumulation of cholesteryl ester in
diseases are discussed in detail below. liver eventually leading to chronic liver disease (Fouchier and

Encyclopedia of Cell Biology, Volume 1 doi:10.1016/B978-0-12-394447-4.10021-5 173

174 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids

OH O
O HO OH
O
HO
HO
H
H
H H
H H H
O
O
H H Cortisol
Aldosterone
HO
Cholesterol
O OH
O
H
H
H H H
H H HO
H H HO Estradiol
O
Pregnenolone
Progesterone

OH

H H
O
Testosterone
Figure 1 Structure of cholesterol and other steroids.

Defesche, 2013). Proper formation, transport, and hydrolysis Phospholipid

of cholesteryl esters are essential in overall cholesterol
homeostasis in the body.
Cholesterol

Cholesterol in Cell Membranes

Cholesterol levels within the cell membrane influence the

biophysical properties of the membrane and play a critical role Figure 2 Cholesterol in plasma membrane.
in cell membrane ordering, permeability, phase transitions,
and in maintaining cell membrane integrity. The plasma membrane inhibits the internalization of clathrin-coated pits
membrane is made up of phospholipid bilayer, proteins, (Subtil et al., 1999). Thus, cholesterol not only alters the
cholesterol, glycoproteins, and glycolipids (Figure 2). Chol- properties of the cell membrane but plays an active role in the
esterol is not arranged uniformly throughout the plasma functional aspect of the cell membrane.
membrane, but is found in varying concentrations. The hy-
droxyl group of cholesterol in phospholipid bilayer is oriented
toward the hydrophilic head of the phospholipids in the Cholesterol Biosynthesis
membrane. At high temperatures, cholesterol reduces phos-
pholipid movement and prevents the membrane from be- Cholesterol synthesis, also called cholesterologenesis, is a
coming too fluid or permeable. However, at low temperature, multistep enzymatic biosynthetic process that begins with
cholesterol prevents crystallization of membranes that can acetyl-coenzyme A. A simplified schematic of the pathway that
occur due to close packing of fatty acid tails. Cholesterol has displaces the most important steps is shown in Figure 3.
also been shown to be associated with sphingolipids to form Cholesterol synthesis takes place in the cytoplasm and in the
lipid rafts (George and Wu, 2012; Brown and London, 2000). endoplasmic reticulum (ER). The first step in the pathway
These rafts have an important role in protein interaction dur- catalyzed by 3-hydroxy-3-methylglutaryl (HMG)-CoA syn-
ing cell signaling (Lemaire-Ewing et al., 2012; Simons and thase (HMGCS) occurs in the cytosol while the subsequent
Toomre, 2000; George and Wu, 2012). Moreover, cholesterol steps occur in the ER. Thus, the ER is the main site of chol-
has been recognized as an essential modulator of sonic esterol synthesis (Simons and Ikonen, 2000). Cholesterol
hedgehog signaling. It is also required for the formation of synthesis begins with acetyl-coenzyme A derived from mito-
clathrin-coated pits in cell membranes during endocytosis. chondria and transported to the cytosol. One molecule of
There is direct evidence that depletion of cholesterol in the acetyl-coenzyme A and one molecule of acetoacetyl-CoA are
 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids 175

Acetyl-CoA
HMGCS Cholesterol

HMG-CoA DHCR7
HMGCR

Mevalonic acid 7-Dehydrocholesterol DHCR24

MVK SC5DL

Mevalonic acid-5P
Lathosterol Desmosterol
PMVK

Mevalonic acid 5-pyrophosphate

MVD Lanosterol
Isopentenyl pyrophosphate
LSS
IDI1
(S)-2,3-Epoxysqualene
FDPS
Dimethylallyl pyrophosphate
SQLE
FDPS

Geranyl pyrophosphate Farnesyl pyrophosphate Squalene

FDPS FDFT1

Enzymes

Figure 3 Cholesterol biosynthesis pathway.

converted to HMG-CoA. HMG-CoA is then reduced to meva- mediated by changes in HMGCR. High cholesterol levels cause
lonate by HMG-CoA reductase (HMGCR). Mevalonate is fur- reduction in transcription of HMGCR gene, leading to the re-
ther phosphorylated to isopentyl pyrophosphate, which is duction in the amount of HMGCR (messenger RNA) mRNA.
converted to geranyl pyrophosphate. Condensation with an- HMGCR activity is also regulated through phosphorylation.
other isopentyl pyrophosphate yields farnesyl pyrophosphate. AMP (adenosine monophosphate)-dependent protein kinase
Squalene synthase catalyzes the condensation of two mol- (AMPK) catalyzes the phosphorylation and inhibition of the
ecules of farnesyl pyrophosphate to yield squalene. Squalene is enzyme (Motoshima et al., 2006). Various cholesterol metab-
then cyclized to form lanosterol. Finally lanosterol is con- olites such as oxidized derivatives of cholesterol as well as
verted to cholesterol in 19 more reactions. cholesterol biosynthesis intermediates such as mevalonate and
HMGCR is the rate-limiting enzyme of the pathway. It farnesol are additional components of the negative feedback
is tightly regulated at transcriptional and posttranscri- loop that regulates the levels of HMGCR (Correll et al., 1994).
ptional levels. Mechanisms such as phosphorylation–depho- Cholesterol can also induce ubiquitination and degradation of
sphorylation, feedback from sterol and non-sterol metabolites HMGCR. Increases in cellular cholesterol concentrations trig-
of the pathway, and ubiquitination control the activity and gers binding of HMGCR to the ER membrane proteins Insig-1
levels of HMGCR. This enzyme is a pharmacological target of a and Insig-2. This binding leads to the recruitment of gp78, the
class of drugs called statins, which are commonly used to ubiquitin ligase that leads to ubiquitination of the enzyme. In
lower cholesterol by reducing cholesterol biosynthesis. Statins this manner, HMGCR is marked for degradation and trans-
are competitive inhibitors of HMGCR enzyme. ported to proteasomes for degradation (DeBose-Boyd, 2008).
The cholesterol biosynthesis pathway yields several mol- A complex of proteins that sense cellular cholesterol levels
ecules as intermediates that are essential for other biological also regulates the rate of cholesterol synthesis. Sterol response
pathways. Farnesyl and geranylgeranyl membrane anchors are element binding protein (SREBP), the SREBP cleavage acti-
important for signaling proteins that regulate progression vating protein (SCAP), and two SREBP-specific proteases (S1P
through cell cycle (Edwards and Ericsson, 1999). Ubiquinone and S2P) are the key components of this pathway (Horton
and dolichols are other intermediates that have roles in elec- et al., 2002; Bengoechea-Alonso and Ericsson, 2007). SREBP
tron transport and synthesis of glycoproteins, respectively. precursor proteins are embedded in the membrane of ER. The
Cholesterol can be further modified into steroid hormones as N-terminal domain of SREBP acts as a transcription factor,
well as vitamin D. whereas the C-terminal domain interacts with C-terminal do-
main of another ER protein SCAP, which contains a sterol-
sensing domain. As shown in Figure 4, when sterol levels are
Regulation of Cholesterol Biosynthesis high, SCAP interacts with ER membrane protein, insulin
regulated protein (Insig) (Yang et al., 2002). Association with
The complex regulation of cholesterol biosynthesis takes place Insig leads to the retention of SREBP–SCAP complex in the ER
at several levels. The rate of synthesis is highly responsive to (Yang et al., 2002). When sterol levels are low, SCAP and Insig
cellular level of cholesterol. There exists a feedback regulation do not interact, which leads to a conformational change in
176 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids

INSIG SCAP SREBP

High cholesterol Low cholesterol

INSIG SCAP SREBP INSIG SCAP SREBP

ER retention Transport to golgi

Proteolytic processing

Nucleus

HMGCR
SRE LDLR
Figure 4 SREBP and SCAP in transcriptional control of cholesterol synthesis.

SCAP (Brown et al., 2002). The SREBP–SCAP complex then endocytosis. LDL particles and their receptors have an important
translocates from ER to Golgi apparatus (Figure 4). Two pro- role in cholesterol homeostasis (Go and Mani, 2012). Genetic
teases, S1P and S2P, act on SREBP in the Golgi apparatus mutation in the LDL receptor is associated with a condition
(Nohturfft et al., 2000). SREBP is first cleaved by protease S1P, called familial hypercholesterolemia, which is associated with
yielding a product that then acts as a substrate for protease increased atherosclerosis and heart disease. LDL-derived chol-
S2P. This cleaved SREBP is then released to the cytosol and esterol is shown to inhibit HMGCR gene transcription by in-
travels to the nucleus where it binds to sterol response element hibiting SREBP pathway (Brown and Goldstein, 1980).
(SRE) DNA sites resulting in increased transcription of several Increased LDL cholesterol leads to the reduction of synthesis of
genes involved in cholesterol synthesis pathway (Bengoechea- LDLR through negative feedback mechanism. When the chol-
Alonso and Ericsson, 2007). esterol level in cells is low, more LDLRs are produced that help
take up LDL from plasma. Along with inhibiting HMGCR, sta-
tins upregulate LDLR resulting in clearing of LDL from the cir-
Cellular Cholesterol Homeostasis culation. These LDLRs undergo endocytosis taking LDL inside
the cell through endosome and are later released from endo-
In addition to intracellular synthesis, cholesterol can also enter some and are either degraded or released back to the surface
the cells through uptake of cholesterol-containing lipoproteins (Ikonen, 2008). Due to the cellular toxicity of free cholesterol,
from plasma. A simplified schematic of cholesterol homeo- excess free cholesterol must be esterified (by the enzyme ACAT)
stasis is presented in Figure 5. Cholesterol from diet is ab- and packaged in lipid droplets (Chang et al., 1997).
sorbed in the intestine, solubilized in micelles, and LDL particles undergo a range of modifications. Oxidized
transported to the periphery packaged in the form of chylo- LDL particles are specifically targeted for uptake by scavenger
microns along with triglycerides (Wang, 2007). The enzyme receptors found in macrophages. These help reduce the
lipoprotein lipase interacts with chylomicrons and hydrolyzes amount of plasma LDL cholesterol and return them to the liver
triglycerides to release fatty acids. The resulting chylomicron in the form of HDL, another lipoprotein particle, via a process
remnants enter hepatocytes by binding to apolipoprotein E called reverse cholesterol transport. HDL particles play a crit-
receptors. Cholesterol is subjected to endocytosis and is either ical role in reverse cholesterol transport where cholesterol is
converted to bile acids, secreted into circulation, esterified, or returned to the liver from the periphery. Nascent HDL particles
packaged into very low-density lipoprotein (VLDL) particles. interact with cholesterol transporter proteins on the cell sur-
These VLDL particles containing cholesterol and triglycerides face, ATP-binding cassette, sub-family A, member 1 (ABCA1),
are secreted into circulation. Interaction of VLDL particles with and ATP-binding cassette, sub-family G, member 1 (ABCG1),
lipases results in change in the composition of these particles. and accept cholesterol. The enzyme LCAT in HDL converts free
These particles contain less triglycerides and all apolipopro- cholesterol to cholesteryl esters and stores them in the HDL
teins are lost except apolipoprotein B (ApoB). These modified core. A defect in ABCA1 gene is associated with Tangier dis-
particles are called LDLs. LDL particles are responsible for ease, which is associated with very low levels of HDL and high
transporting cholesterol to the periphery. risk of atherosclerosis. Cholesterol transported back to the liver
LDL particles are mostly composed of cholesterol esters. is either recycled, stored, or converted to bile acids.
Cells that require cholesterol express receptors that recognize Nuclear receptors such as liver X-receptors (LXR), farnesoid
and bind LDL particles resulting in receptor-mediated X-receptor (FXR), and peroxisome proliferator-activated
 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids 177

VLDL

Liver

VLDL
Blood vessel

LDL
Peripheral tissue

HDL

LDL
HDL
Bile
Chylomicron

Intestine LDL

HDL
Feces

LDL

Macrophage
Figure 5 Overview of cholesterol homeostasis.

receptor γ (PPARγ) are crucial in cholesterol homeostasis. LXRs Unlike other peripheral organs, cholesterol is recycled at a
are activated by cholesterol derivatives, oxysterols. LXRs are very high rate in the brain. As a result, the half-life of choles-
transcription factors and regulate the expression of important terol in adult brain is about five years (Björkhem et al., 1998).
genes such as ABCA1, ABCG1, and ApoE important in the While most of the cholesterol is recycled, the brain
process of reverse cholesterol transport (Laffitte et al., 2001; also excretes some cholesterol in the form of 24(S)-hydro-
Beyea et al., 2007). FXRs play a role in bile acid metabolism xycholesterol. Cholesterol is converted to 24(S)-hydro-
and in regulation of cholesterol removal from body. The xycholesterol by the CYP46 (cholesterol 24-hydroxylase)
ability of these nuclear receptors to affect cholesterol metab- enzyme. As evident from numerous studies, cholesterol me-
olism makes them an attractive therapeutic target for treatment tabolism in the brain is independent of that in rest of the body
of metabolic diseases associated with dyslipidemia. (Björkhem et al., 1998; Dietschy and Turley, 2001). The im-
portance of separate cholesterol regulatory mechanisms in
brain is still not completely understood. However, tight
Cholesterol in Brain regulation of cholesterol synthesis in brain appears to be
critical and defects in cholesterol metabolism have been im-
The brain contains approximately one-fourth of the total plicated in many neurological disorders.
amount of cholesterol in the body, making it the most chol-
esterol-rich organ. Cholesterol is a major component of the
myelin sheath and is crucial for proper brain development Cholesterol in Diseases
(Dietschy and Turley, 2001). A distinct pool of cholesterol is
maintained in the brain by local de novo synthesis. The blood– Many pathological conditions are associated with abnormal
brain barrier prevents the exchange of lipoproteins in the cir- cholesterol levels or impaired cholesterol metabolism in the
culation, thus the brain must maintain its own cholesterol body. Some of these are briefly discussed below.
transport system. In adult brain, astrocytes synthesize most of Cardiovascular diseases: Elevated cholesterol levels are as-
the cholesterol and send them to neurons in ApoE-containing sociated with cardiovascular conditions such as atherosclerotic
lipoproteins particles. Cholesterol released from astrocytes plaque formation, stroke, and myocardial infarction. For-
through ABCA1 and ABCG1 transporters are shuttled to neu- mation of atherosclerotic plaque is an intricate process in-
rons and taken up by receptor-mediated endocytosis via LDLR volving inflammation and lipid deposition that eventually
family receptors. narrows the arteries which results in luminal obstruction.
178 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids

Hypercholesterolemia is a well-established risk factor for the Steroids

incidence of atherosclerosis and its pathologic complications.
Modified LDL is taken up by mature macrophages in the ar- Cholesterol is the precursor of numerous sterol molecules such
tery. These macrophages accumulate in the subendothelial as oxysterols, bile acids, and steroid hormones. These choles-
space and become cholesterol-laden foam cells that eventually terol metabolites function as activators of nuclear receptors,
harden and become plaques. Statins (inhibitors of HMGCR) regulate expression of genes in lipid and fat metabolism, have
that effectively lower plasma cholesterol are the most com- important function in bile acid synthesis and steroid hormone
monly prescribed drug. production, and are required for the transport of sterols from
Cholesterol gallstone disease (Cholelithiasis): Gallstones peripheral tissues such as brain to the liver.
are masses of cholesterol crystals, calcium bilirubinate, and Bile acids are oxidized derivatives of cholesterol. These are
proteins. Gallstones are formed as a result of excess cholesterol amphipathic molecules required for processing of dietary fat
in bile or due to insufficient bile acids. This condition is highly and for maintaining cholesterol homeostasis. Conversion of
prevalent in developed countries. Dyslipidemia is one of the cholesterol into bile is the only mechanism of cholesterol ex-
major risk factors of cholesterol gallstones. cretion from the body. Bile is formed in the liver by the action
Familial hypercholesteremia: Mutations within the low- of many enzymes and cholesterol 7-alpha hydroxylase
density lipoprotein receptor gene are one of the major causes (CYP7A1) is the rate-limiting enzyme for bile acid synthesis
of familial hypercholesteremia. Due to the defect in this re- (Jelinek et al., 1990).
ceptor, LDL accumulates in the plasma leading to enhanced Cholesterol also serves as a precursor for all steroid hor-
atherosclerosis. mones. These hormones regulate many important physio-
Tangier disease: Mutations in the gene encoding the chol- logical processes such as stress response, cognition, ion
esterol transporter ABCA1 result in very low levels of HDL balance, secondary sexual characteristics, electrolyte balance,
particles in blood (Bodzioch et al., 1999). Tangier disease is and carbohydrate metabolism. Steroid hormones are pro-
inherited as an autosomal recessive trait. There is excessive duced primarily in response to trophic hormones in several
accumulation of cholesterol in several parts of the body due to steroidogenic tissues including adrenal cortex, testes, ovary,
impaired reverse cholesterol transport and the disease is as- placenta, and brain.
sociated with increased atherosclerosis. During steroid synthesis, cholesterol in the cell is trans-
SLOS: SLOS is a developmental disorder characterized by ported to the mitochondria where the enzyme Cyp11 converts
several physical, mental, and behavioral abnormalities related it to pregnenolone, which is the common precursor of all
to deficiency of cholesterol synthesis. DHCR7 codes for the steroid hormones (Figure 6; Miller and Auchus, 2011). Since
enzyme involved in the last step in cholesterol synthesis. cholesterol cannot travel from outer to inner mitochondrial
Mutation in this gene causes the buildup of the 7-dehy- membrane due to its hydrophobicity, the delivery of choles-
drocholesterol metabolite, resulting in insufficient cholesterol terol to the inner membrane is the rate-limiting step in ster-
synthesis; both combined are responsible for the multiple oidogenesis. The enzyme steroidogenic acute regulatory
developmental disorders. protein (STAR) regulates this rate-limiting step by facilitating
Neurological disorders: Defects in cholesterol metabolism in the transfer of cholesterol into the inner membrane of mito-
the brain have been associated with many neurological disorders chondria (Stocco, 2001; Miller and Auchus, 2011).
such as Alzheimer's disease, Parkinson's disease, Huntington's Testosterone, progesterone, estradiol, cortisol, and al-
disease, Niemen-Pick disease, and SLOS (Vance, 2012). The dosterone are five major classes of steroids. These hormones
complexity of these diseases together with very limited know- are all derived from pregnenolone and control a wide variety
ledge of cholesterol metabolism in brain has proved to be a of physiological processes. Progesterone is required for main-
major challenge for scientists trying to study the pathology of the tenance of pregnancy, follicular growth, and ovulation and is
disease. produced by ovarian cells and corpus luteum (Graham and

Cholesterol

Pregnenolone 17-Hydroxypregnenolone Dehydroepiandrosterone

Progesterone 17-Hydroxyprogesterone Androstenedione

11-Deoxycorticosterone
11-Deoxycortisol Testosterone

Corticosterone
Cortisol Estradiol

Aldosterone
Figure 6 The biosynthetic pathway of steroid hormones.
 Molecular Principles, Components, Technology, and Concepts: Lipids: Cholesterol and Other Steroids 179

Clarke, 1997). Cortisol is produced by adrenal cortex and has a Dowhan, W., Bogdanov, M., Mileykovskaya, E., 2008. Functional roles of lipids in
number of diverse functions including modulating blood membranes. Biochemistry of Lipids, Lipoproteins and Membranes. Amsterdam:
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Edwards, P.A., Ericsson, J., 1999. Sterols and isoprenoids: Signaling molecules
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larly, estrogen, produced by ovary, is required for the main- hypercholesterolaemic phenotype. Current Opinion in Lipidology 24, 332–338.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/23652569 (accessed 24.02.15).
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also found to be important for maintaining bone integrity. Toxicology and Applied Pharmacology 259, 311–319.
Finally, aldosterone, produced in adrenal cortex, regulates Graham, J.D., Clarke, C.L., 1997. Physiological action of progesterone in target
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Ginsburg, G.S., Atkinson, D., Small, D.M., 1984. Physical properties of cholesteryl
kidney and sweat glands (Müller, 1995). Apart from these
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Ikonen, E., 2008. Cellular cholesterol trafficking and compartmentalization. Nature
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See also: Molecular Principles, Components, Technology, Jelinek, D.F., Andersson, S., Slaughter, C.A., Russell, D.W., 1990. Cloning and
regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile
and Concepts: Lipids: Lipidomics acid biosynthesis. Journal of Biological Chemistry 265, 8190–8197.
Laffitte, B.A., Repa, J.J., Joseph, S.B., et al., 2001. LXRs control lipid-inducible
expression of the apolipoprotein E gene in macrophages and adipocytes.
Proceedings of the National Academy of Sciences of the United States of
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