Cholesterol

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Cholesterol

IUPAC name[hide]

(3β)-cholest-5-en-3-ol

Other names[hide]

(10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,
9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta
[a]phenanthren-3-ol

Identifiers

CAS number 57-88-5

PubChem 5997

ChemSpider 5775
UNII 97C5T2UQ7J

KEGG D00040

ChEMBL CHEMBL112570

Jmol-3D
Image 1
images

SMILES

[show]

InChI
[show]

Properties

Molecular
C27H46O
formula

Molar mass 386.65 g/mol

Appearance white crystalline powder[1]

Density 1.052 g/cm3

Melting point 148–150 °C[1]

Boiling point 360 °C (decomposes)

Solubility in
0.095 mg/L (30 °C)
water

soluble in acetone, benzene, chloroform,

Solubility ethanol, ether, hexane, isopropyl myristate,
methanol

(what is this?) (verify)

Except where noted otherwise, data are given for materials in
their standard state (at 25 °C, 100 kPa)

Infobox references
Microscopic appearance of cholesterol crystals in water. Photo taken under polarized light.

Cholesterol is a waxy steroid of fat that is manufactured in the liver or intestines. It is used to
produce hormones and cell membranes and is transported in the blood plasma of all mammals.[2]
It is an essential structural component of mammalian cell membranes. It is required to establish
proper membrane permeability and fluidity. In addition cholesterol is an important component
for the manufacture of bile acids, steroid hormones, and Vitamin D. Cholesterol is the principal
sterol synthesized by animals however small quantities can be synthesized in eukaryotes such as
plants and fungi. It is almost completely absent among prokaryotes including bacteria.[3]
Although cholesterol is important and necessary for mammals, high levels of cholesterol in the
blood can damage arteries and are potentially linked to diseases such as those associated with the
cardiovascular system (heart disease).[4]

The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the
chemical suffix -ol for an alcohol. François Poulletier de la Salle first identified cholesterol in
solid form in gallstones, in 1769. However, it was only in 1815 that chemist Eugène Chevreul
named the compound "cholesterine".[5]

Contents
[hide]

• 1 Physiology
o 1.1 Function
o 1.2 Dietary sources
o 1.3 Synthesis
o 1.4 Regulation of cholesterol synthesis
o 1.5 Plasma transport and regulation of absorption
o 1.6 Metabolism, recycling and excretion
• 2 Significance
o 2.1 Hypercholesterolemia
o 2.2 Hypocholesterolemia
o 2.3 Cholesterol testing
• 3 Interactive pathway map
• 4 Cholesteric liquid crystals
• 5 See also
 • 6 Additional images
• 7 References

• 8 External links

[edit] Physiology
Since cholesterol is essential for all animal life, it is primarily synthesized from simpler
substances within the body. However, high levels in blood circulation, depending on how it is
transported within lipoproteins, are strongly associated with progression of atherosclerosis. For a
person of about 68 kg (150 pounds), typical total body cholesterol synthesis is about 1 g
(1,000 mg) per day, and total body content is about 35 g. Typical daily additional dietary intake
in the United States is 200–300 mg.[citation needed] The body compensates for cholesterol intake by
reducing the amount synthesized.

Cholesterol is recycled. It is excreted by the liver via the bile into the digestive tract. Typically
about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the
bloodstream. Phytosterols can compete with cholesterol reabsorption in the intestinal tract, thus
reducing cholesterol reabsorption.[6]

[edit] 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. In this structural role, cholesterol reduces the permeability of the plasma
membrane to protons (positive hydrogen ions) and sodium ions.[7]

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
(MβCD) 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. 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.[8]

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, Vitamin A, Vitamin D, Vitamin E, and Vitamin 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 that cholesterol may act as an antioxidant.[9]

[edit] 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.[10] Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry,
and shrimp.[11]

Human breast milk also contains significant quantities of cholesterol.[12]

The amount of cholesterol present in plant-based food sources is generally much lower than
animal based sources.[11][13] In addition, plant products such as flax seeds and peanuts contain
cholesterol-like compounds called phytosterols, which are suggested to help lower serum
cholesterol levels.[14]

Total fat intake, especially saturated fat and trans fat,[15] plays a larger role in blood cholesterol
than intake of cholesterol itself. Saturated fat is present in full fat dairy products, animal fats,
several types of oil and chocolate. Trans fats are typically derived from the partial hydrogenation
of unsaturated fats, and do not occur in significant amounts in nature. Trans fat is most often
encountered in margarine and hydrogenated vegetable fat, and consequently in many fast foods,
snack foods, and fried or baked goods.

A change in diet in addition to other lifestyle modifications may help reduce blood cholesterol.
Avoiding animal products may decrease the cholesterol levels in the body not only by reducing
the quantity of cholesterol consumed but also by reducing the quantity of cholesterol
synthesized. Those wishing to reduce their cholesterol through a change in diet should aim to
consume less than 7% of their daily energy needs {metric units Joules (J) or (kJ), pre-SI calories
(Cal) or (kcal)} from animal fat and fewer than 200 mg of cholesterol per day.[16]

It is debatable that a diet, changed to reduce dietary fat and cholesterol, can lower blood
cholesterol levels,[4] (and thus reduce the likelihood of development of, among others, coronary
artery disease leading to coronary heart disease), because any reduction to dietary cholesterol
intake could be counteracted by the organs compensating to try to keep blood cholesterol levels
constant.[17] Also pointed out is the experimental discovery that in the diet, ingested animal
protein can raise blood cholesterol more than the ingested saturated fat or any cholesterol.[18]
Moreover, the benefits of a diet supplemented with plant sterol esters has been questioned.[19][20]

[edit] Synthesis

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 dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).
This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step 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. This molecule 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 then converted to cholesterol.[21]

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.

[edit] 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).[22] 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 SRE (sterol regulatory element), 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
HMG-CoA reductase leads to an increase of endogenous production of cholesterol.[23] 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 be turned off when cholesterol levels are high, as well. HMG CoA
reductase contains both a cytosolic domain (responsible for its catalytic function) and a
membrane domain. The membrane domain functions to sense 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.[24]

[edit] Plasma transport and regulation of absorption

See also: Blood lipids

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 which 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 within 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 cholesterol 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 which is not used by muscles remains in more cholesterol-rich
chylomicron remnants, which are taken up from 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 shell. During transport in the bloodstream, the
blood vessel 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 into
metabolism 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 that 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 artherosclerotic plaque
formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis
(carotid intima-media thickness).[25] 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.[24]

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).[26] Having large numbers of large HDL particles correlates with better health
outcomes.[27] In contrast, having small numbers of large HDL particles is independently
associated with atheromatous disease progression within the arteries.

[edit] Metabolism, recycling and excretion

Cholesterol is susceptible to oxidation and easily forms oxygenated derivatives known as

oxysterols. Three different mechanisms can form these; autoxidation, secondary oxidation to
lipid peroxidation, and cholesterol metabolizing enzyme oxidation. A great interest in oxysterols
arose when it was shown they exert inhibitory actions on cholesterol biosynthesis,[28]. 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.[29]

Cholesterol is oxidized by the liver into a variety of bile acids.[30] These in turn are conjugated
with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and non-conjugated
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.[31]
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.[32]

[edit] Significance
[edit] Hypercholesterolemia

Main articles: hypercholesterolemia and lipid hypothesis

According to the lipid hypothesis, abnormal cholesterol levels (hypercholesterolemia)—that is,
higher concentrations of LDL and lower concentrations of functional HDL—are strongly
associated with cardiovascular disease because these promote atheroma development in arteries
(atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke, and
peripheral vascular disease. Since higher blood LDL, especially higher LDL particle
concentrations and smaller LDL particle size, contribute to this process more than the cholesterol
content of the LDL particles,[33] LDL particles are often termed "bad cholesterol" because they
have been linked to atheroma formation. On the other hand, high concentrations of functional
HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes
referred to as "good cholesterol". These balances are mostly genetically determined but can be
changed by body build, medications, food choices, and other factors.[34]

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense
LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a
condition known as atherosclerosis, which is the principal cause of coronary heart disease and
other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have
been identified as a mechanism by which cholesterol and inflammatory mediators can be
removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma
progressions and even regression. A 2007 study pooling data on almost 900,000 subjects in 61
cohorts demonstrated that blood total cholesterol levels have an exponential effect on
cardiovascular and total mortality, with the association more pronounced in younger subjects.
Still, because cardiovascular disease is relatively rare in the younger population, the impact of
high cholesterol on health is still larger in older people.[35]

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic
(prone to cause atherosclerosis).[36] Levels of these fractions, rather than the total cholesterol
level, correlate with the extent and progress of atherosclerosis. On the converse, the total
cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL
particles, under which conditions atheroma growth rates would still be high. In contrast,
however, if LDL particle number is low (mostly large particles) and a large percentage of the
HDL particles are large, then atheroma growth rates are usually low, even negative, for any
given total cholesterol concentration.[citation needed] Recently, a post-hoc analysis of the IDEAL and
the EPIC prospective studies found an association between high levels of HDL cholesterol
(adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular
disease, casting doubt on the cardioprotective role of "good cholesterol".[37]

Elevated cholesterol levels are treated with a strict diet consisting of low-saturated fat, trans-fat
free, low cholesterol foods,[38][39] often followed by one of various hypolipidemic agents such as
statins, fibrates, cholesterol absorption inhibitors, nicotinic acid derivatives or bile acid
sequestrants.[40] Extreme cases have previously been treated with partial ileal bypass surgery,
which has now been superseded by medication. Apheresis-based treatments are still used for
very severe hyperlipidemias that are either unresponsive to treatment or require rapid lowering of
blood lipids.[citation needed]

Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have
repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier
patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol
values currently considered low for adults.[citation needed] As a result, people with a history of
cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels,[41]
and in men without cardiovascular disease there is benefit from lowering abnormally high
cholesterol levels ("primary prevention").[42] Primary prevention in women is practiced only by
extension of the findings in studies on men,[43] since in women, none of the large statin trials has
shown a reduction in overall mortality or in cardiovascular end points.[44]

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the
total blood cholesterol level should be: < 200 mg/dL normal blood cholesterol, 200–239 mg/dL
borderline-high, > 240 mg/dL high cholesterol.[45] The American Heart Association provides a
similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:[46]

Level mg/dL Level mmol/L Interpretation

< 200 < 5.0 Desirable level corresponding to lower risk for heart disease
200–240 5.2–6.2 Borderline high risk
> 240 > 6.2 High risk

However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol
separately, this simplistic view has become somewhat outdated. The desirable LDL level is
considered to be less than 100 mg/dL (2.6 mmol/L),[47] although a newer upper limit of 70 mg/dL
(1.8 mmol/L) can be considered in higher risk individuals based on some of the above-mentioned
trials. A ratio of total cholesterol to HDL—another useful measure—of far less than 5:1 is
thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to
develop is 35 mg/dL.[citation needed]

Reference ranges for blood tests, showing usual as well as optimal levels of HDL, LDL and total
cholesterol in mass and molar concentrations, found in orange color at right, that is, among the
blood constituents with the highest concentration.

Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Usually, only the total, HDL,
and triglycerides are measured. For cost reasons, the VLDL is usually estimated as one-fifth of
the triglycerides and the LDL is estimated using the Friedewald formula (or a variant): estimated
LDL = [total cholesterol] − [total HDL] − [estimated VLDL]. VLDL can be calculated by
dividing total triglycerides by 5. Direct LDL measures are used when triglycerides exceed
400 mg/dL. The estimated VLDL and LDL have more error when triglycerides are above
400 mg/dL.[48]

Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some
studies have shown an inverse correlation between cholesterol levels and mortality. A 2009 study
of patients with acute coronary syndromes found an association of hypercholesterolemia with
better mortality outcomes.[49] In the Framingham Heart Study, in subjects over 50 years of age
they found an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year
drop in total cholesterol levels. The researchers attributed this phenomenon to the fact that
people with severe chronic diseases or cancer tend to have below-normal cholesterol levels.[50]
This explanation is not supported by the Vorarlberg Health Monitoring and Promotion
Programme, in which men of all ages and women over 50 with very low cholesterol were
increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that
the low-cholesterol effect occurs even among younger respondents, contradicting the previous
assessment among cohorts of older people that this is a proxy or marker for frailty occurring with
age.[51]

The vast majority of doctors and medical scientists consider that there is a link between
cholesterol and atherosclerosis as discussed above;[52] a small group of scientists, united in The
International Network of Cholesterol Skeptics, questions the link.[53]

[edit] Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes
of this state is relatively limited, but some studies suggest a link with depression, cancer, and
cerebral hemorrhage. In general, the low cholesterol levels seem to be a consequence of an
underlying illness, rather than a cause.[35]

[edit] Cholesterol testing

The examples and perspective in this section report US measures, whereas the measure
in many places is mmol/L, into which they need to be converted, therefore the section
may not represent a worldwide view of the subject. Please improve this article and
discuss the issue on the talk page. (October 2009)

It is recommended by the American Heart Association to test cholesterol every 5 years for
people aged 20 years or older.[54]

A blood sample after 12-hour fasting is taken by a doctor or a home cholesterol-monitoring

device to determine a lipoprotein profile. This measures total cholesterol, LDL (bad) cholesterol,
HDL (good) cholesterol, and triglycerides. It is recommended to test cholesterol at least every 5
years if a person has total cholesterol of 200 mg/dL or more, or if a man over age 45 or a woman
over age 50 has HDL (good) cholesterol less than 40 mg/dL, or there are other risk factors for
heart disease and stroke. (In different countries measurements are given in mg/dL or mmol/L;
1 mmol/L is 38.665 mg/dL.)

[edit] Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [55]
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Statin Pathway [edit]

[edit] Cholesteric liquid crystals

Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the
liquid crystalline cholesteric phase. The cholesteric phase is in fact a chiral nematic phase, and
changes colour when its temperature changes. This makes cholesterol derivatives useful for
indicating temperature in liquid crystal display thermometers and in temperature-sensitive paints.

[edit] See also

• Arcus senilis "Cholesterol ring" in the eyes
• Bile salts
• Diet and heart disease
• Lieberman–Burchard test to detect cholesterol
• Niemann–Pick disease Type C
• Triglycerides
• Vertical Auto Profile
• oxycholesterol
• Cholesterol total synthesis

[edit] Additional images

Steroidogenesis, using cholesterol as building material

Space-filling model of the Cholesterol molecule

• Numbering of the steroid nuclei

Hypercholesterolemia
From Wikipedia, the free encyclopedia
(Redirected from Hypercholesterolaemia)
Jump to: navigation, search

Hypercholesterolemia

Classification and external resources

Formula structure of cholesterol

ICD-10 E78.0

ICD-9 272.0

DiseasesDB 6226

eMedicine med/1073

MeSH D006937

Hypercholesterolemia is the presence of high levels of cholesterol in the blood.[1] It is not a

disease but a metabolic derangement that can be caused by many diseases, notably
cardiovascular disease. It is closely related to the terms "hyperlipidemia" (elevated levels of
lipids in the blood) and "hyperlipoproteinemia" (elevated levels of lipoproteins in the blood).[1]
Elevated cholesterol in the blood is due to abnormalities in the levels of lipoproteins, the
particles that carry cholesterol in the bloodstream. This may be related to diet, genetic factors
(such as LDL receptor mutations in familial hypercholesterolemia) and the presence of other
diseases such as diabetes and an underactive thyroid. The type of hypercholesterolemia depends
on which type of particle (such as low-density lipoprotein) is present in excess.[1]

Hypercholesterolemia is treated by reducing dietary cholesterol intake, administration of certain

medications, and rarely with other treatments including surgery (for particular severe subtypes).

Contents
[hide]

• 1 Classification
• 2 Signs and symptoms
• 3 Causes
o 3.1 Diet
o 3.2 Genetics
• 4 Diagnosis
• 5 Screening
• 6 Treatment
o 6.1 Lifestyle
o 6.2 Medication
o 6.3 Guidelines
o 6.4 Alternative medicine

• 7 References

[edit] Classification
Main article: Hyperlipidemia

Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the

Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis" have offered
significant improvements in understanding the connection with atherosclerosis progression and
clinical consequences.

If the hypercholesterolemia is hereditary (familial hypercholesterolemia), there is more often a

family history of premature, earlier onset atherosclerosis.

[edit] Signs and symptoms

Xanthelasma palpebrarum, yellowish patches consisting of cholesterol deposits above the
eyelids. These are more common in people with familial hypercholesterolemia.

Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum

cholesterol can lead to atherosclerosis.[2] Over a period of decades, chronically elevated serum
cholesterol contributes to formation of atheromatous plaques in the arteries. This leads to
progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries.
Blood supply to the tissues and organs served by these stenotic or occluded arteries gradually
diminishes until organ function becomes impaired. It is at this point that tissue ischemia
(restriction in blood supply) may manifest as specific symptoms. For example, temporary
ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as
temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking),
paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body.
Insufficient blood supply to the heart may manifest as chest pain, and ischemia of the eye may
manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as
calf pain when walking, while in the intestines it may present as abdominal pain after eating a
meal.[1][3] Some types of hypercholesterolemia lead to specific physical findings. For example,
familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with
xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids),[4] arcus
senilis (white or gray discoloration of the peripheral cornea),[5] and xanthomata (deposition of
yellowish cholesterol-rich material) of the tendons, especially of the fingers.[6][7] Type III
hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.[6]

[edit] Causes
Hypercholesterolemia is typically due to a combination of environmental and genetic factors.[2]
Environmental factors include: obesity and dietary choices.[2] Genetic contributions are usually
due to the additive effects of multiple genes however occasionally may be due to a single gene
defect such as in the case of familial hypercholesterolaemia.[2] A number of secondary causes
exist including: diabetes mellitus type 2, obesity, alcohol, monoclonal gammopathy, dialysis,
nephrotic syndrome, obstructive jaundice, hypothyroidism, Cushing’s syndrome, anorexia
nervosa, medications (thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic
acid).[2]

[edit] Diet
While part of the circulating cholesterol originates from diet, and restricting cholesterol intake
may reduce blood cholesterol levels, there are various other links between the dietary pattern and
cholesterol levels.

[edit] Genetics

Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such
as in familial hypercholesterolemia where there is one or more genetic mutations in, for example,
the LDL receptor.

Even when there is no single responsible mutation to explain hypercholesterolemia, genetic

predisposition still plays a major role, potentially adding to lifestyle factors and multiplying the
risk of late complications. Multiple genes are involved, and hypercholesterolemia where there is
probably a genetic predisposition is called polygenic hypercholesterolemia. The involved genes
have yet to be discovered.[8]

[edit] Diagnosis
See also: High-density lipoprotein#Recommended ranges and Low-density lipoprotein#Normal
ranges

Two bags of fresh frozen plasma. The bag on the left was obtained from a donor with
hypercholesterolemia, while the other bag was obtained from a donor with normal serum lipid
levels.

There is not an absolute cutoff between normal and abnormal cholesterol levels and
interpretation of values needs to occur in relation to other health factors. The ideal cholesterol
level should be less than 4 mmol/l with a LDL cholesterol less than 2 mmol/l in those at high risk
of cardiovascular disease.[2]

Higher cholesterol levels lead to increased risk of several diseases, most notably cardiovascular
diseases. Specifically, high levels of small LDL cholesterol particles are associated with
increased risk.[9][10] Larger LDL particles do not carry the same risk.

When measuring cholesterol, it is important to measure its subfractions before drawing a

conclusion as to the cause of the problem. The subfractions are LDL, HDL and VLDL. In the
past, LDL and VLDL levels were rarely measured directly due to cost concerns. VLDL levels
are reflected in the levels of triglycerides (generally about 45% of triglycerides is composed of
VLDL). LDL was usually estimated as a calculated value from the other fractions (total
cholesterol minus HDL and VLDL); this method is called the Friedewald calculation; to be
specific: LDL ~= Total Cholesterol - HDL - (0.2 x Triglycerides).
Less expensive (and less accurate) laboratory methods and the Friedewald calculation have long
been used because of the complexity, labor, and expense of the electrophoretic methods
developed in the 1970s to identify the different lipoprotein particles that transport cholesterol in
the blood. In 1980, the original methods, developed by research work in the mid-1970s cost
about $5,000, in US 1980 dollars, per blood sample/person.

With time, more advanced laboratory analyses that do measure LDL and VLDL particle sizes
and levels have been developed, and at far lower cost. These have partly been developed and
become more popular as a result of the increasing clinical trial evidence that intentionally
changing cholesterol transport patterns, including to certain abnormal values compared to most
adults, often has a dramatic effect on reducing, even partially reversing, the atherosclerotic
process. With ongoing research and advances in laboratory methods, the prices for more
sophisticated analyses have markedly decreased, to less than $100, US 2004, by some labs, and
with simultaneous increases in the accuracy of measurement for some of the methods.

[edit] Screening
Screening for a disease refers to testing for a disease, such as hypercholesterolemia, in patients
who have no signs or symptoms of the disease. In patients without any other risk factors,
moderate hypercholesterolemia is often not treated. According to Framingham Heart Study,
people with an age greater than 50 years have no increased overall mortality with either high or
low serum cholesterol levels. There is, however, a correlation between falling cholesterol levels
over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD
death rate increase per 1 mg/dL per year drop in cholesterol levels). This, however, does not
mean that a decrease in serum levels is dangerous, as there has not yet been a recorded heart
attack in the study in a person with a total cholesterol below 150 mg/dL.

The U.S. Preventive Services Task Force (USPSTF) has evaluated screening for
hypercholesterolemia. They strongly recommends that clinicians routinely screen men aged 35
years and older and women aged 45 years and older for lipid disorders and treat abnormal lipids
in people who are at increased risk of coronary heart disease (level A recommendation). They
also recommend that clinicians routinely screen younger adults (men aged 20 to 35 years and
women aged 20 to 45 years) for lipid disorders if they have other risk factors for coronary heart
disease (level B recommendation).[11][12]

Two factors for consideration when choosing therapy are a persons risk of coronary disease and
their lipoprotein pattern.

• Risk of coronary disease: To calculate the benefit of treatment, there are online
calculators that can estimate baseline risk.[13][14] Combining the baseline risk with the
relative risk reduction of a treatment can lead to the absolute risk reduction of number
needed to treat. For example, one of the calculators projects that a patient had a 10% risk
of coronary disease over ten years. As noted below, the relative risk reduction of a statin
is 30%. Thus, after 4–7 years of treatment with a statin, a patient's risk will drop to 7%.
This equates to an absolute risk reduction of 3%, or a number needed to treat of 33.
Thirty three such patients must be treated for 4–7 years for one to benefit.
 • Lipoprotein patterns: (See hyperlipoproteinemia for details) The treatment depends on the
type of hypercholesterolemia. This has led to the concept of dyslipidemia, despite normo-
cholesterolemia. Thus there has been increasing recognition of the importance of
"lipoprotein subclass analysis" as an important approach to better understand and change
the connection between cholesterol transport and atherosclerosis progression. Fredrickson
Types IIa and IIb can be treated with diet, statins, cholesterol absorption inhibitors
(ezetimibe), fibrates, vitamin B3 (niacin), bile acid sequestrants (colestipol,
cholestyramine), LDL apheresis and in severe hereditary cases liver transplantation.

[edit] Treatment
Recommendations for both primary prevention[15] and secondary prevention [16] have been
published. For those at high risk a combination of lifestyle modification and statins has been
shown to decrease mortality.[2]

[edit] Lifestyle

A number of lifestyle changes are recommended in those with high cholesterol including:
smoking cessation, limiting alcohol consumption, physical activity, maintaining a healthy
weight, and a diet low in saturated fats.[2]

In strictly controlled surroundings, a diet can reduce cholesterol levels by 15%. In practice,
dietary advice can provide a modest decrease in cholesterol levels and may be sufficient in the
treatment of mildly elevated cholesterol.[17]

[edit] Medication

While statins are effective in decreasing mortality in those who have had previous cardiovascular
disease, there is debate over whether or not they are effective in those with high cholesterol but
no other health problems.[18] One review did not find a mortality benefit in those at high-risk but
without prior cardiovascular disease.[18] Other reviews concluded that there is a mortality
benefit[19] but there was concerns regarding the quality of the evidence.[20] With respect to quality
of life there is limited evidence of improvement when statins are used for primary prevention.[20]
No studies as of 2010 show improved clinical outcomes in children with high cholesterol even
though statins decrease cholesterol levels.[21]

[edit] Guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The
American College of Physicians has addressed hypercholesterolemia in patients with diabetes.[22]
Their four recommendations are:

1. Lipid-lowering therapy should be used for secondary prevention of cardiovascular

mortality and morbidity for all patients (both men and women) with known coronary
artery disease and type 2 diabetes.
 2. Statins should be used for primary prevention against macrovascular complications in
patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
3. Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be
taking at least moderate doses of a statin (the accompanying evidence report states
"simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d;
or an equivalent dose of another statin").[23]
4. For those patients with type 2 diabetes who are taking statins, routine monitoring of liver
function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their guidelines;[24] however, their 2004
revisions have been criticized for use of nonrandomized, observational data.[25]

In the UK, the National Institute for Health and Clinical Excellence (NICE) has made
recommendations for the treatment of elevated cholesterol levels, published in 2008.[26]

[edit] Alternative medicine

According to a survey in 2002, alternative medicine was used in an attempt to treat cholesterol
by 1.1% of U.S. adults. Consistent with previous surveys, this one found that the majority of
individuals (i.e., 55%) used it in conjunction with conventional medicine.[27] A review trials of
phytosterols and/or phytostanols reported an average of 9% lowering of LDL-cholesterol.[28] In
2000 the Food and Drug Administration approved the labeling of foods containing specified
amounts of phytosterol esters or phytostanol esters as cholesterol lowering; in 2003 an FDA
Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering
more than 0.8 grams/day of phytosterols or phytostanols. Some researchers, however, are
concerned about diet supplementation with plant sterol esters and draw attention to significant
safety issues.[citation needed] Health Canada does not allowed the sale of foods enriched with plant
sterol esters.[29]