Cholesterol - Wikipedia, The Free Encyclopedia

8/9/2019 Cholesterol - Wikipedia, The Free Encyclopedia

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Cholesterol

(3)- cholest- 5- en- 3- ol

(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

SMILES

O[C@@H]4C/C3=C/C[C@@H]1[C@H](CC[C@]2([C@H]1CC[C@@H]2[C@H](C)CCCC(C)C)C)[C@@]3(C)CC4

InChI1/C27H46O/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28)13-15-26(20,4)25(22)14-16-27(23,24)5/h9,18-

Cholesterol

From Wikipedia, the free encyclopedia

Cholesterol is a waxy steroid metabolite

found in the cell membranes andtransported in the blood plasma of all

animals.[2] It is an essential structural

component of mammalian cell

membranes, where 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 fat-

soluble vitamins including Vitamin A,Vitamin D, Vitamin E, and Vitamin K.

Cholesterol is the principal sterol

synthesized by animals, but small

quantities are synthesized in other

eukaryotes, such as plants and fungi. It is

almost completely absent among

prokaryotes, which include bacteria.[3]

Although cholesterol is an important and

necessary molecule for animals, a highlevel of serum cholesterol is an indicator

for diseases such as heart disease.

The name cholesterol originates from the

Greekchole- (bile) andstereos (solid),

and the chemical suffix -olfor an alcohol,

as Franois Poulletier de la Salle first

identified cholesterol in solid form in

gallstones, in 1769. However, it was onlyin 1815 that chemist Eugne Chevreul

IUPAC name

Other names

25-08-2010 Cholesterol - Wikipedia, the free encyclopedia

http://en.wikipedia.org/wiki/Cholesterol 1/14


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19,21-25,28H,6-8,10-17H2,1-5H3/t19-,21+,22+,23-,24+,25+,26+,27-/m1/s1

InChI key HVYWMOMLDIMFJA-DPAQBDIFBB

Properties

Molecular

formula

C27H46O

Molar mass 386.65 g/mol

Appearance white crystalline powder[1]

Density 1.052 g/cm3

Melting

point 148150 C[1]

Boiling

point 360 C (decomposes)

Solubility in

water

0.095 mg/L (30 C)

Solubility soluble in acetone, benzene, chloroform, ethanol, ether, hexane, isopropyl myristate, methanol

(what is this?) (verify) (http://en.wikipedia.org/w/index.php?title=Cholesterol&diff=cur&oldid=329028259)

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.

named the compound "cholesterine".[4]

Contents

1 Physiology

1.1 Overview1.2 Function

1.3 Dietary sources

1.4 Synthesis

1.5 Regulation of

cholesterol synthesis

1.6 Plasma transport

and regulation of

absorption

1.7 Metabolism,

recycling and excretion

2 Interactive pathway map

3 Clinical significance

3.1

Hypercholesterolemia

3.2

Hypocholesterolemia

3.3 Cholesterol testing

4 Cholesteric liquid crystals

5 See also

6 Additional images

7 References

8 External links

Physiology




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Overview

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 200300 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 cholesterol reabsorption in intestinal tract back into the intestinal lumen for

elimination.[5]

Function

Cholesterol is required to build and maintain membranes; it regulates 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. [6]

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 (MCD) 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.[7]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in thegallbladder. 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.[8]

Dietary sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat




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contain cholesterol to varying extents.[9] Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp.[10]

Human breast milk also contains significant quantities of cholesterol.[11]

The amount of cholesterol is present in plant-based food sources is generally much lower than animal based sources. [10][12] 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. [13]

Total fat intake, especially saturated fat and trans fat, [14] 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, in contrast to other types of fat, do not occur in significant amounts in nature. Research supports a recommendation to minimize or eliminate trans

fats from the diet due to their adverse health effects. [15] 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 levels of animal-based food consumed and 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

calories from saturated fat and less than 200 mg of cholesterol per day. [16]

The view that a change in diet (to be specific, a reduction in dietary fat and cholesterol) can lower blood cholesterol levels, and thus reduce the likelihood

of development of, among others, coronary artery disease (CHD) has been challenged. An alternative view is that any reductions to dietary cholesterol

intake are counteracted by the organs such as the liver, which will increase or decrease production of cholesterol to keep blood cholesterol levels

constant.[17] Another view is that although saturated fat and dietary cholesterol also raise blood cholesterol, these nutrients are not as effective at doing

this as is animal protein.[18]

Synthesis

About 2025% of total daily cholesterol production occurs in the liver; other sites of high 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 ofsqualene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally, lanosterol is then converted to




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cholesterol.[19]

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).[20] 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.[21] 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.[22]

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 spherical 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.




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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 vessels cleave and

absorb more triacylglycerol to leave IDL molecules, which contain an even higher percentage of cholesterol. The IDL molecules have two possible fates:

Half are taken up by the liver for metabolism into other biomolecules 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 LDLmolecules 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. 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.[22]

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).[23] Having large numbers of large HDL particles correlates with better health outcomes. [24] In

contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.




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Metabolism, recycling and excretion

Cholesterol is oxidized by the liver into a variety of bile acids.[25] 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 lost in the feces.[26] 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 less frequently.

[27]

Interactive pathway map

Click on genes, proteins and metabolites below to v isit Gene Wiki pages and related Wikipedia articles. The pathway can be downloaded and

edited at WikiPathways (http://www.wikipathways.org/index.php/Pathway:WP430) .

Statin Pathway [edit

(http://www.wikipathways.org/index.php/Pathway:WP430) ]




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Clinical significance

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 offunctional HDLare 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,[28] 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.[29]

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.[30]

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis).[31] 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"[32]

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,[33] and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").[34] Primary

prevention in women is practiced only by extension of the findings in studies on men,[35] since in women, none of the large statin trials has shown a




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Level mg/dL Level mmol/L Interpretation

< 200 < 5.0 Desirable level corresponding to lower risk for heart disease

200240 5.26.2 Borderline high risk

> 240 > 6.2 High risk

reduction in overall mortality or in cardiovascular end points.[36]

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, 200239 mg/dL borderline-high, > 240 mg/dL high cholesterol.[37] The American Heart Association provides a similar set of

guidelines for total (fasting) blood cholesterol levels and risk for heart disease:[38]

However, as today's testing methods determine LDL

("bad") and HDL ("good") cholesterol separately, thissimplistic view has become somewhat outdated. The

desirable LDL level is considered to be less than

100 mg/dL (2.6 mmol/L)[39], although a newer target of

Cholesterol - Wikipedia, The Free Encyclopedia

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