Cholesterol, from the Ancient Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol, is an organic molecule. It is a sterol
(or modified steroid), and an essential structural component of animal cell membranes that is required to establish proper membrane permeability and fluidity.
In addition to its importance
within cells, cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D. Cholesterol is
the principal sterol synthesized by animals; in vertebrates it is formed predominantly in the liver. It is almost completely absent
among prokaryotes (i.e., bacteria), although there are some
exceptions such as Mycoplasma, which require cholesterol for growth. François Poulletier de
la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until 1815 that
chemist Michel Eugène Chevreul named the compound "cholesterine".
Physiology
Since cholesterol is essential for
all animal life, each cell synthesizes it from simpler molecules, a complex
37-step process that starts with the intracellular protein enzyme HMG-CoA reductase.
However, normal and particularly high levels of fats (including cholesterol) in
the blood circulation, depending on how they are transported within lipoproteins, are
strongly associated with the progression of atherosclerosis.
For a man of about 68 kg (150
pounds), typical total body-cholesterol synthesis is approximately 1 g
(1,000 mg) per day, and total body content is approximately 35 g,
primarily located within the membranes of all the cells of the body. Typical
daily dietary intake of additional cholesterol, in the United States, is
200–300 mg.
Most ingested cholesterol is
esterified, and esterified cholesterol is poorly absorbed. The body also
compensates for any absorption of additional cholesterol by reducing
cholesterol synthesis. For these reasons, cholesterol intake in food has
little, if any, effect on total body cholesterol content or concentrations of
cholesterol in the blood.
Cholesterol is recycled. The liver excretes it
in a non-esterified form (via bile) into the digestive tract. Typically the
small bowel back into the bloodstream reabsorbs about 50% of the excreted
cholesterol.
Some plants make
cholesterol in very small amounts. Plants manufacture phytosterols
(substances chemically similar to cholesterol produced within plants), which
can compete with cholesterol for reabsorption in the intestinal tract, thus
potentially reducing cholesterol reabsorption. When intestinal lining cells
absorb phytosterols, in place of cholesterol, they usually excrete the
phytosterol molecules back into the GI tract, an
important protective mechanism.
Function
Cholesterol is
required to build and maintain membranes; it modulates membrane fluidity over
the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane,
alongside the nonpolar fatty-acid chain of
the other lipids. Through the interaction with the phospholipid fatty-acid
chains, cholesterol increases membrane packing, which reduces membrane
fluidity. The structure of the tetracyclic ring of cholesterol contributes to
the decreased fluidity of the cell membrane as the molecule is in a trans
conformation making all but the side chain of cholesterol rigid and planar. In
this structural role, cholesterol reduces the permeability of the plasma
membrane to neutral solutes, protons, (positive hydrogen ions) and sodium ions.
Within the cell membrane,
cholesterol also functions in intracellular transport, cell signaling and nerve
conduction. Cholesterol is essential for the structure and function of
invaginated caveolae and clathrin-coated pits, including
caveola-dependent and clathrin-dependent endocytosis. The role of cholesterol in such
endocytosis can be investigated by using methyl beta
cyclodextrin (MBCD) to remove cholesterol from the
plasma membrane. Recently, cholesterol has also been implicated in cell
signaling processes, assisting in the formation of lipid rafts in the plasma membrane. Lipid raft formation brings
receptor proteins in close proximity with high concentrations of second
messenger molecules. In many neurons, a myelin sheath, rich in cholesterol, since it
is derived from compacted layers of Schwann cell membrane, provides insulation for
more efficient conduction of impulses.
Within cells, cholesterol is the
precursor molecule in several biochemical pathways. In the liver, cholesterol
is converted to bile,
which is then stored in the gallbladder. Bile contains bile salts, which
solubilize fats in the digestive tract and aid in the intestinal absorption of
fat molecules as well as the fat-soluble vitamins, A, D, E, and K. Cholesterol is an important precursor
molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.
Some research indicates cholesterol may act as
an antioxidant.
Dietary sources
Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and
cholesterol. As a consequence, all foods containing animal fat contain
cholesterol to varying extents. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, fish,
and shrimp. Human breast milk also contains significant quantities of
cholesterol.
From a dietary perspective, cholesterol is not
found in significant amounts in plant sources. In addition, plant products such
as flax seeds and peanuts contain cholesterol-like compounds
called phytosterols, which are believed to compete
with cholesterol for absorption in the intestines. Phytosterols can be supplemented through the use of
phytosterol-containing functional foods or nutraceuticals that
are widely recognized as having a proven LDL cholesterol-lowering
efficacy. Current supplemental guidelines recommend doses of phytosterols in
the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a
recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a
mean dose of 2.15 gram per day. However, the benefits of a diet
supplemented with phytosterol has been questioned.
Fat intake also plays a role in
blood-cholesterol levels. This effect is thought[by whom?] to
come about by changes in the quantity of cholesterol and lipoproteins that are synthesized by the body.
Isocalorically replacing dietary carbohydrates with monounsaturated and polyunsaturated fats
has been shown to lower serum LDL and
total cholesterol levels and increase serum HDL levels,
while replacing carbohydrates with saturated fat was
shown to increase HDL, LDL, and total cholesterol levels. Trans fats have been shown to reduce levels of HDL
while increasing levels of LDL. Based on such evidence and evidence implicating
low HDL and high LDL levels in cardiovascular
disease (see Hypercholesterolemia),
many health authorities advocate reducing LDL cholesterol through changes in
diet in addition to other lifestyle modifications. The USDA,
for example, recommends that those wishing to reduce their cholesterol through
a change in diet should aim to consume less than 7% of their daily energy needs
from saturated fat and fewer than
Biosynthesis
All animal cells manufacture cholesterol with relative
production rates varying by cell type and organ function. About 20–25% of total
daily cholesterol production occurs in the liver; other sites of higher synthesis rates
include the intestines, adrenal glands, and reproductive
organs. Synthesis within the body starts with one molecule of acetyl CoA and one
molecule of acetoacetyl-CoA,
which are hydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This
molecule is then reduced to mevalonate by the
enzyme HMG-CoA reductase.
This is the regulated, rate-limiting and irreversible step in cholesterol
synthesis and is the site of action for the statin drugs
(HMG-CoA reductase competitive inhibitors).
Mevalonate is then converted to 3-isopentenyl pyrophosphate
in three reactions that require ATP. Mevalonate is decarboxylated to isopentenyl pyrophosphate, which is a key metabolite
for various biological reactions. Three molecules of isopentenyl pyrophosphate
condense to form farnesyl pyrophosphate through
the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then
condense to form squalene by the
action of squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then
cyclizes squalene to form lanosterol. Finally,
lanosterol is converted to cholesterol through a 19-step process.
Konrad
Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964
for their discoveries concerning the mechanism and regulation of cholesterol
and fatty acid metabolism.
Regulation of cholesterol synthesis
Biosynthesis of cholesterol is directly regulated by the
cholesterol levels present, though the homeostatic mechanisms
involved are only partly understood. A higher intake from food leads to a net
decrease in endogenous production, whereas lower intake from food has the
opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol
in the endoplasmic reticulum by the protein SREBP (sterol
regulatory element-binding protein 1 and 2). In the
presence of cholesterol, SREBP is bound to two other proteins: SCAP
(SREBP-cleavage-activating protein) and Insig1. When cholesterol levels fall, Insig-1
dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus,
where SREBP is cleaved by S1P and S2P (site-1 and -2 protease), two enzymes
that are activated by SCAP when cholesterol levels are low. The cleaved SREBP
then migrates to the nucleus and acts as a transcription
factor to bind to
the sterol regulatory element (SRE), which stimulates the transcription of many
genes. Among these are the low-density lipoprotein (LDL) receptor and HMG-CoA reductase.
The former scavenges circulating LDL from the bloodstream, whereas the latter
leads to an increase of endogenous production of cholesterol. A large
part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph
L. Goldstein in the
1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their
work. Their subsequent work shows how the SREBP pathway regulates expression of
many genes that control lipid formation and metabolism and body fuel
allocation.
Cholesterol synthesis can also be turned off
when cholesterol levels are high. HMG CoA reductase contains both a cytosolic
domain (responsible for its catalytic function) and a membrane domain. The
membrane domain senses signals for its degradation. Increasing concentrations
of cholesterol (and other sterols) cause a change in this domain's
oligomerization state, which makes it more susceptible to destruction by the proteosome. This
enzyme's activity can also be reduced by phosphorylation by an AMP-activated
protein kinase. Because this kinase is activated by
AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol
synthesis is halted when ATP levels are low.
Plasma transport and
regulation of absorption
See also: Blood lipids
Blood lipids (or blood fats) are lipids in the blood, either free or
bound to other molecules. They are mostly transported in a protein capsule[citation needed], and the density
of the lipids and type of protein determines the fate of the particle and its
influence on metabolism. The concentration of blood lipids depends on
intake and excretion from the intestine, and uptake and secretion from cells. Blood lipids are mainly fatty acids and cholesterol. Hyperlipidemia is the presence of elevated or
abnormal levels of lipids and/or lipoproteins in the blood, and is a major
risk factor for cardiovascular disease.[citation needed]
Cholesterol is only slightly soluble in water; it can dissolve and travel in the
water-based bloodstream at exceedingly small concentrations. Since cholesterol
is insoluble in blood, it is transported in the circulatory system within lipoproteins,
complex discoidal particles that have an exterior composed of amphiphilic proteins
and lipids whose outward-facing surfaces are water-soluble and inward-facing
surfaces are lipid-soluble;triglycerides and
cholesterol esters are carried internally. Phospholipids and cholesterol, being
amphipathic, are transported in the surface monolayer of the lipoprotein particle.
In addition to providing a soluble means for transporting
cholesterol through the blood, lipoproteins have cell-targeting signals that
direct the lipids they carry to certain tissues. For this reason, there are
several types of lipoproteins in blood, called, in order of increasing density, chylomicrons,very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The
more lipid and less protein a lipoprotein has, the less dense it is. The
cholesterol within all the various lipoproteins is identical, although some
cholesterol is carried as the "free" alcohol and some is carried as
fatty acyl esters referred to as cholesterol esters. However, the different
lipoproteins contain apolipoproteins,
which serve as ligands for specific receptors on cell membranes. In this way,
the lipoprotein particles are molecular addresses that determine the start- and
endpoints for cholesterol transport.
Chylomicrons, the least dense type of cholesterol transport
molecules, contain apolipoprotein
B-48, apolipoprotein C,
and apolipoprotein E in their
shells. Chylomicrons are the transporters that carry fats from the intestine to
muscle and other tissues that need fatty acids for energy or fat production.
Cholesterol that is not used by muscles remains in more cholesterol-rich
chylomicron remnants, which are taken up from here to the bloodstream by the
liver.
VLDL molecules are produced by the liver and contain excess
triacylglycerol and cholesterol that is not required by the liver for synthesis
of bile acids. These molecules contain apolipoprotein
B100 and
apolipoprotein E in their shells. During transport in the bloodstream, the
blood vessels cleave and absorb more triacylglycerol from IDL molecules, which
contain an even higher percentage of cholesterol. The IDL molecules have two
possible fates: Half are metabolized by HTGL, taken up by the LDL receptor on the
liver cell surfaces, and the other half continue to lose triacylglycerols in
the bloodstream until they form LDL molecules, which have the highest
percentage of cholesterol within them.
LDL molecules, therefore, are the major carriers of
cholesterol in the blood, and each one contains approximately 1,500 molecules
of cholesterol ester. The shell of the LDL molecule contains just one molecule
of apolipoprotein B100, which is recognized by the LDL receptor in
peripheral tissues. Upon binding of apolipoprotein B100, many LDL receptors
become localized in clathrin-coated
pits. Both the LDL and its receptor are internalized by endocytosis to form a
vesicle within the cell. The vesicle then fuses with a lysosome, which has
an enzyme called lysosomal acid lipase that hydrolyzes
the cholesterol esters. Now within the cell, the cholesterol can be used for
membrane biosynthesis or esterified and stored within the cell, so as to not
interfere with cell membranes.
Synthesis of the LDL receptor is regulated by SREBP, the same regulatory protein as was used
to control synthesis of cholesterol de novo in
response to cholesterol presence in the cell. When the cell has abundant
cholesterol, LDL receptor synthesis is blocked so new cholesterol in the form
of LDL molecules cannot be taken up. On the converse, more LDL receptors are
made when the cell is deficient in cholesterol. When this system is
deregulated, many LDL molecules appear in the blood without receptors on the
peripheral tissues. These LDL molecules are oxidized and taken up by macrophages, which
become engorged and form foam cells. These cells often become trapped in the
walls of blood vessels and contribute to atherosclerotic plaque formation.
Differences in cholesterol homeostasis affect the development of early
atherosclerosis (carotid intima-media thickness). These
plaques are the main causes of heart attacks, strokes, and other serious
medical problems, leading to the association of so-called LDL cholesterol
(actually a lipoprotein) with
"bad" cholesterol.
Also, HDL particles are thought to transport
cholesterol back to the liver for excretion or to other tissues that use
cholesterol to synthesize hormones in a process known as reverse cholesterol transport (RCT). Having large numbers of large HDL particles correlates
with better health outcomes. In contrast, having small numbers of large HDL
particles is independently associated with atheromatous disease progression in the arteries.
Metabolism, recycling
and excretio
Cholesterol is susceptible to oxidation and easily forms
oxygenated derivatives known as oxysterols. Three
different mechanisms can form these; autoxidation, secondary oxidation to lipid per-oxidation and cholesterol-metabolizing enzyme oxidation. A great interest
in oxysterols arose when they were shown to exert inhibitory actions on
cholesterol biosynthesis. This
finding became known as the “oxysterol hypothesis”. Additional roles for
oxysterols in human physiology include their: participation in bile acid
biosynthesis, function as transport forms of cholesterol, and regulation of
gene transcription.
In biochemical experiments radio labelled forms of
cholesterol, such as tritiated-cholesterol are used. These derivatives undergo
degradation upon storage and it is essential to purify cholesterol prior to
use. Cholesterol can be purified using small Sephadex LH-20 columns.
Cholesterol is oxidized by the liver into a variety of bile acids. These,
in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture
of conjugated and nonconjugated bile acids, along with cholesterol itself, is
excreted from the liver into the bile. Approximately 95% of the bile acids are
reabsorbed from the intestines, and the remainder are lost in the feces. The
excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation, which is essential for the
digestion and absorption of dietary fats. Under certain circumstances, when
more concentrated, as in the gallbladder,
cholesterol crystallises and is the major constituent of most gallstones.
Although, lecithin and bilirubin gallstones
also occur, but less frequently. Every day, up to 1 g of cholesterol enters the
colon. This cholesterol originates from the diet, bile, and desquamated
intestinal cells, and can be metabolized by the colonic bacteria. Cholesterol
is converted mainly into coprostanol, a
nonabsorbable sterol that is excreted in the feces. A cholesterol-reducing
bacterium origin has been isolated from human feces.
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