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CholesterolFrom Wikipedia, the free encyclopedia

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Cholesterol

Names

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Identifiers

model=C%5BC%40H%5D%28CCCC%28C%29C%29%5BC%40H%5D1CC%5BC%40%40H%5D2%5BC%40%40%5D1%28CC%5BC%40H%5D3%5BC%40H%5D2CC%3DC4%5BC%40%40%5D3%28CC%5BC%40%40H%5D%28C4%29O%29C%29C)

Properties

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Hazards

Microscopic appearance ofcholesterol crystals in water.Photo taken under polarized light.

Cholesterol, from the Ancient Greek chole­ (bile) and stereos (solid) followed by the chemical suffix ­olfor an alcohol, is an organic molecule. It is a sterol (or modified steroid),[4] a lipid molecule and isbiosynthesized by all animal cells because it is an essential structural component of all animal (not plant orbacterial) cell membranes that is required to maintain both membrane structural integrity and fluidity.Cholesterol enables animal cells to (a) not need a cell wall (like plants and bacteria) to protect membraneintegrity/cell­viability, thus are able to (b) change shape and (c) move about (unlike bacteria and plantcells which are restricted by their cell walls).

In addition to its importance within cells, cholesterol also serves as a precursor for the biosynthesis ofsteroid hormones, bile acids, and vitamin D.[5] Cholesterol is the principal sterol synthesized by animals.All kinds of cells in animals can produce it. In vertebrates the hepatic cells typically produce greateramounts than other cells. It is almost completely absent among prokaryotes (bacteria and archaea),although there are some exceptions such as Mycoplasma, which require cholesterol for growth.[6]

François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until 1815 that chemistMichel Eugène Chevreul named the compound "cholesterine".[7][8]

Contents

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1 Physiology1.1 Function1.2 Dietary Sources1.3 Biosynthesis1.4 Regulation of cholesterol synthesis1.5 Plasma transport and regulation of absorption1.6 Metabolism, recycling and excretion

2 Clinical significance2.1 Hypercholesterolemia2.2 Hypocholesterolemia2.3 Cholesterol testing

3 Interactive pathway map4 Cholesteric liquid crystals5 Stereoisomers6 See also7 Additional images8 References9 External links

Physiology

Since cholesterol is essential for all animal life, each cell synthesizes it through a complex process beginning with mevalonate pathway andending with the 19 step conversion of lanosterol to cholesterol. 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 (arterioscleroticvascular disease).

A human male weighing 68 kg (150 lb) normally synthesises about 1 g (1,000 mg) per day, and his body contains about 35 g, mostly containedwithin the cell membranes. Typical cholesterol dietary intake for a man in the United States is 307 mg, which is above the upper limitrecommended by the Dietary Guidelines Advisory Committee.[9]

Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. The body also compensates for any absorption ofadditional cholesterol by reducing cholesterol synthesis.[10] For these reasons, seven to ten hours after ingestion, cholesterol will show little, ifany, effect on total body cholesterol content or concentrations of cholesterol in the blood. However, during the first seven hours after ingestionof cholesterol, the levels significantly increase.[11]

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Cholesterol is recycled. The liver excretes it in a non­esterified form (via bile) into the digestive tract. Typically, about 50% of the excretedcholesterol is reabsorbed by the small bowel back into the bloodstream.

Plants make cholesterol in very small amounts.[12] Plants manufacture phytosterols (substances chemically similar to cholesterol producedwithin plants), which can compete with cholesterol for reabsorption in the intestinal tract, thus potentially reducing cholesterol reabsorption.[13]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. Thehydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroidand the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty­acid chain of the other lipids. Through the interactionwith the phospholipid fatty­acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.[14] The structure of thetetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making allbut the side chain of cholesterol rigid and planar.[15] In this structural role, cholesterol reduces the permeability of the plasma membrane toneutral solutes,[16] hydrogen ions, and sodium ions.[17]

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Cholesterol is essential forthe structure and function of invaginated caveolae and clathrin­coated pits, including caveola­dependent and clathrin­dependent endocytosis.The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from theplasma membrane. Recent studies show that cholesterol is also implicated in cell signaling processes, assisting in the formation of lipid rafts inthe plasma membrane. Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messengermolecules.[18] 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.[19]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is thenstored in the gallbladder. Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat moleculesas well as the fat­soluble vitamins, A, D, E, and K. Cholesterol is an important precursor molecule for the synthesis of vitamin D and thesteroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, andtestosterone, and their derivatives.[5]

Some research indicates cholesterol may act as an antioxidant.[20]

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Dietary Sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foodscontaining animal fat contain cholesterol to varying extents.[21] Major dietary sources of cholesterol include cheese, egg yolks, beef, pork,poultry, fish, and shrimp.[22] Human breast milk also contains significant quantities of cholesterol.[23]

From a dietary perspective, cholesterol is not found in significant amounts in plant sources.[22][24] In addition, plant products such as avocado,[25] flax seeds and peanuts contain cholesterol­like compounds called phytosterols, which are believed to compete with cholesterol forabsorption in the intestines, thus reducing the absorption of both dietary and bile cholesterol.[26] Phytosterols can be supplemented through theuse of phytosterol­containing functional foods or nutraceuticals that are widely recognized as having a proven LDL cholesterol­loweringefficacy.[27] Current supplemental guidelines recommend doses of phytosterols in the 1.6­3.0 grams per day range (Health Canada, EFSA,ATP III,FDA) with a recent meta­analysis demonstrating an 8.8% reduction in LDL­cholesterol at a mean dose of 2.15 gram per day.[28]

However, the benefits of a diet supplemented with phytosterol has been questioned.[29][30]

The fraction of dietary cholesterol which is absorbed varies from 15% to 75%, and is about 50% on average, with the remainder excreted in thefeces.[31] Free cholesterol is much more likely to be absorbed than esterified cholesterol, and the proportion of free versus esterified cholesterolvaries between different food sources.[32] In February 2015, reversing decades­long recommendations, the USDA Dietary Guidelines AdvisoryCommittee recommended repealing the guideline that Americans limit cholesterol intake, because dietary cholesterol intake was not found tocorrelate well with serum cholesterol levels. The committee found strong evidence that replacing saturated fat with unsaturated fat wouldlower LDL cholesterol levels, and that low­fat diets which replace saturated fat with carbohydrates would lower both LDL and HDLcholesterol levels.[33] Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.[34] Based on such evidence andevidence implicating low HDL and high LDL levels in cardiovascular disease (see Hypercholesterolemia), many health authorities advocatereducing LDL cholesterol through changes in diet in addition to other lifestyle modifications.[35]

Biosynthesis

All animal cells manufacture cholesterol for their use, with relative production rates varying by cell type and organ function. About 20–25% oftotal daily cholesterol production occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands, andreproductive organs. Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl CoA condense to formacetoacetyl­CoA. This is followed by a second condensation between acetyl CoA and acetoacetyl­CoA to form 3­hydroxy­3­methylglutarylCoA (HMG­CoA).[36] This molecule is then reduced to mevalonate by the enzyme HMG­CoA reductase. Production of mevalonate is the rate­limiting and irreversible step in cholesterol synthesis and is the site of action for statins (a class of cholesterol lowering drugs).

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Mevalonate is finally converted to isopentenyl pyrophosphate (IPP) through two phosphorylation steps and one decarboxylation step thatrequires ATP. Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyltransferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmicreticulum.[36] Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally, lanosterol is converted to cholesterol through a 19­stepprocess.[37][38]

Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanismand 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 partlyunderstood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the oppositeeffect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterolregulatory element­binding protein 1 and 2).[39] In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBPcleavage­activating protein) and INSIG­1. When cholesterol levels fall, INSIG­1 dissociates from the SREBP­SCAP complex, which allowsthe complex to migrate to the Golgi apparatus. Here SREBP is cleaved by S1P and S2P (site­1 protease and site­2 protease), two enzymes thatare 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), whichstimulates the transcription of many genes. Among these are the low­density lipoprotein (LDL) receptor and HMG­CoA reductase. The LDLreceptor scavenges circulating LDL from the bloodstream, whereas HMG­CoA reductase leads to an increase of endogenous production ofcholesterol.[40] A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In1985, they received the Nobel Prize in Physiology or Medicine for their work. Their subsequent work shows how the SREBP pathwayregulates 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. HMG­CoA reductase contains both a cytosolic domain(responsible for its catalytic function) and a membrane domain. The membrane domain senses signals for its degradation. Increasingconcentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible todestruction by the proteosome. This enzyme's activity can also be reduced by phosphorylation by an AMP­activated protein kinase. Becausethis kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levelsare low.[41]

Plasma transport and regulation of absorption

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See also: Blood lipids

Cholesterol is only slightly soluble in water; it dissolves into the (water­based) bloodstream only at exceedingly small concentrations. Instead,cholesterol is transported inside lipoproteins, complex discoidal particles with exterior amphiphilic proteins and lipids, whose outward­facingsurfaces are water­soluble and inward­facing surfaces are lipid­soluble. Triglycerides and cholesterol esters are carried internally.Phospholipids and cholesterol, being amphipathic, are transported in the monolayer surface of the lipoprotein particle.

There are several types of lipoproteins in the blood. In order of increasing density, they are chylomicrons, very­low­density lipoprotein(VLDL), low­density lipoprotein (LDL), intermediate­density lipoprotein (IDL), and high­density lipoprotein (HDL). Lower protein/lipidratios make for less dense lipoproteins. Cholesterol within different lipoproteins is identical, although some is carried as "free" alcohol, whileothers as fatty acyl esters, known also as cholesterol esters.

Lipoproteins contain apolipoproteins, which bind to specific receptors on cell membranes, directing their lipid payload to specific tissues.Lipoprotein particles thus include these molecular addresses, which determine the start­ and end points of cholesterol transport.

Chylomicrons, the least dense cholesterol transport molecules, contain apolipoprotein B­48, apolipoprotein C, and apolipoprotein E in theirshells. Chylomicrons carry fats from the intestine to muscle and other tissues in need of fatty acids for energy or fat production. Unusedcholesterol remains in more cholesterol­rich chylomicron remnants, and taken up from here to the bloodstream by the liver.

VLDL molecules are produced by the liver from triacylglycerol and cholesterol which was not used in the synthesis of bile acids. Thesemolecules contain apolipoprotein B100 and apolipoprotein E in their shells, and are degraded by lipoprotein lipase on the blood vessel wall toIDL.

Blood vessels cleave and absorb triacylglycerol from IDL molecules, increasing the concentration of cholesterol. IDL molecules are thenconsumed in two processes: half is metabolized by HTGL and taken up by the LDL receptor on the liver cell surfaces, while the other halfcontinues to lose triacylglycerols in the bloodstream until they become LDL molecules, with the highest concentration of cholesterol withinthem.

LDL particles are the major blood cholesterol carriers. Each one contains approximately 1,500 molecules of cholesterol ester. LDL moleculeshells contain just one molecule of apolipoprotein B100, recognized by LDL receptors in peripheral tissues. Upon binding of apolipoproteinB100, many LDL receptors concentrate in clathrin­coated pits. Both LDL and its receptor form vesicles within a cell via endocytosis. Thesevesicles then fuse with a lysosome, where the lysosomal acid lipase enzyme hydrolyzes the cholesterol esters. The cholesterol can then be usedfor membrane biosynthesis or esterified and stored within the cell, so as to not interfere with the cell membranes.

LDL receptors are used up during cholesterol absorption, and its synthesis is regulated by SREBP, the same protein that controls the synthesisof cholesterol de novo, according to its presence inside the cell. A cell with abundant cholesterol will have its LDL receptor synthesis blocked,to prevent new cholesterol in LDL molecules from being taken up. Conversely, LDL receptor synthesis proceeds when a cell is deficient in

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cholesterol.

When this process becomes unregulated, LDL molecules without receptors begin to appear in the blood. These LDL molecules are oxidizedand taken up by macrophages, which become engorged and form foam cells. These foam cells often become trapped in the walls of bloodvessels and contribute to atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of earlyatherosclerosis (carotid intima­media thickness).[42] These plaques are the main causes of heart attacks, strokes, and other serious medicalproblems, leading to the association of so­called LDL cholesterol (actually a lipoprotein) with "bad" cholesterol.[41]

HDL particles are thought to transport cholesterol back to the liver, either for excretion or for other tissues that synthesize hormones, in aprocess known as reverse cholesterol transport (RCT).[43] Large numbers of HDL particles correlates with better health outcomes.,[44] whereaslow numbers of HDL particles is associated with atheromatous disease progression in the arteries.

Metabolism, recycling and excretion

Cholesterol is susceptible to oxidation and easily forms oxygenated derivatives known as oxysterols. Three different mechanisms can formthese; autoxidation, secondary oxidation to lipid peroxidation, and cholesterol­metabolizing enzyme oxidation. A great interest in oxysterolsarose when they were shown to exert inhibitory actions on cholesterol biosynthesis.[45] This finding became known as the “oxysterolhypothesis”. Additional roles for oxysterols in human physiology include their: participation in bile acid biosynthesis, function as transportforms of cholesterol, and regulation of gene transcription.[46]

In biochemical experiments radiolabelled forms of cholesterol, such as tritiated­cholesterol are used. These derivatives undergo degradationupon storage and it is essential to purify cholesterol prior to use. Cholesterol can be purified using small Sephadex LH­20 columns.[47]

Cholesterol is oxidized by the liver into a variety of bile acids.[48] These, in turn, are conjugated with glycine, taurine, glucuronic acid, orsulfate. 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.[49] The excretion andreabsorption 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 mostgallstones. Although, lecithin and bilirubin gallstones also occur, but less frequently.[50] 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 isconverted mainly into coprostanol, a nonabsorbable sterol that is excreted in the feces. A cholesterol­reducing bacterium origin has beenisolated from human feces.[51]

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Although cholesterol is a steroid generally associated with mammals, the human pathogen Mycobacterium tuberculosis is able to completelydegrade this molecule and contains a large number of genes that are regulated by its presence.[52] Many of these cholesterol­regulated genesare homologues of fatty acid β­oxidation genes, but have evolved in such a way as to bind large steroid substrates like cholesterol.[53][54]

Clinical significance

Hypercholesterolemia

Main articles: hypercholesterolemia and lipid hypothesis

According to the lipid hypothesis, since cholesterol (like all fat molecules) is transported around the body (in the water outside cells) insidelipoprotein particles, elevated cholesterol concentrations (hypercholesterolemia) — potentially offers a lower cost way to detect elevatedconcentrations of LDL particles; possibly even low concentrations of functional HDL particles — both variations strongly associated withcardiovascular disease because LDL particles promote atheroma development in arteries (atherosclerosis).

This atherosclerotic disease process, over decades, leads to myocardial infarction (heart attack), stroke, and peripheral vascular disease. Sincehigher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than thecholesterol content of the HDL particles,[55] LDL particles are often termed "bad cholesterol" because they have been linked to atheromaformation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protectionand 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.[56] Resistin, a protein secreted by fat tissue, has been shown to increase the production of LDL inhuman liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear cholesterol from the bloodstream.Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. Resistin also adversely impacts the effects ofstatins, the main cholesterol­reducing drug used in the treatment and prevention of cardiovascular disease. See:.[57]

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated withatheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease andother forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by whichcholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates ofatheroma progressions and even regression. A 2007 study pooling data on almost 900,000 subjects in 61 cohorts demonstrated that blood totalcholesterol 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 olderpeople.[58]

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Level mg/dL Level mmol/L Interpretation< 200 < 5.2 Desirable level corresponding to lower risk for heart disease200–240 5.2–6.2 Borderline high risk> 240 > 6.2 High risk

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis).[59] Levels ofthese fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterolcan be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rateswould still be high. Recently, a post hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels ofHDL cholesterol (adjusted for apolipoprotein A­I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on thecardioprotective role of "good cholesterol".[60]

Elevated cholesterol levels are treated with a strict diet consisting of low saturated fat, trans fat­free, low cholesterol foods,[61][62] oftenfollowed by one of various hypolipidemic agents, such as statins, fibrates, cholesterol absorption inhibitors, nicotinic acid derivatives or bileacid sequestrants.[63] Extreme cases have previously been treated with partial ileal bypass surgery, which has now been superseded bymedication. Apheresis­based treatments are still used for very severe hyperlipidemias that are either unresponsive to treatment or require rapidlowering of blood lipids.[64]

Multiple human trials using HMG­CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transportpatterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol valuescurrently considered low for adults.[65] Studies have also found that statins reduce atheroma progression.[66] As a result, people with a historyof cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels (total cholesterol below 5.0 mmol/L[193 mg/dL]),[67] and in men without cardiovascular disease, there is benefit from lowering abnormally high cholesterol levels ("primaryprevention").[68] Primary prevention in women was originally practiced only by extension of the findings in studies on men,[69] since, inwomen, none of the large statin trials conducted prior to 2007 demonstrated a statistically significant reduction in overall mortality or incardiovascular endpoints.[70] In 2008, a large clinical trial reported that, in apparently healthy adults with increased levels of the inflammatorybiomarker high­sensitivity C­reactive protein but with low initial LDL, 20 mg/day of rosuvastatin for 1.9 years resulted in a 44% reduction inthe incidence of cardiovascular events and a 20% reduction in all­cause mortality; the effect was statistically significant for both genders.[71]Though this result was met with some skepticism, later studies and meta­analyses likewise demonstrated statistically significant (but smaller)reductions in all­cause and cardiovascular mortality, without significant heterogeneity by gender.[72]

The 1987 report of National Cholesterol EducationProgram, Adult Treatment Panels suggests the totalblood cholesterol level should be: < 200 mg/dLnormal blood cholesterol, 200–239 mg/dLborderline­high, > 240 mg/dL high cholesterol.[73]The American Heart Association provides a similarset of guidelines for total (fasting) bloodcholesterol levels and risk for heart disease:[74]

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However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has becomesomewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L),[75] although a newer upper limit of70 mg/dL (1.8 mmol/L) can be considered in higher­risk individuals based on some of the above­mentioned trials. A ratio of total cholesterolto HDL—another useful measure—of far less than 5:1 is thought to be healthier.

Reference ranges for blood tests, showing usual, as well as optimal, levels of HDL, LDL and totalcholesterol in mass and molar concentrations, is found in orange color at right, that is, among the bloodconstituents 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 costreasons, the VLDL is usually estimated as one­fifth 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 five. DirectLDL measures are used when triglycerides exceed 400 mg/dL. The estimated VLDL and LDL have more error when triglycerides are above400 mg/dL.[76]

Given the well­recognized role of cholesterol in cardiovascular disease, some studies have shown an inverse correlation between cholesterollevels and mortality. A 2009 study of patients with acute coronary syndromes found an association of hypercholesterolemia with bettermortality outcomes.[77] In the Framingham Heart Study, in subjects over 50 years of age, they found an 11% increase overall and 14% increasein cardiovascular disease mortality per 1 mg/dL per year drop in total cholesterol levels. The researchers attributed this phenomenon to the factthat people with severe chronic diseases or cancer tend to have below­normal cholesterol levels.[78] This explanation is not supported by theVorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 with very low cholesterol were likelyto die of cancer, liver diseases, and mental diseases. This result indicates the low­cholesterol 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.[79]

The vast majority of doctors and medical scientists consider that there is a link between cholesterol and atherosclerosis as discussed above;[80]

a small group of scientists, united in The International Network of Cholesterol Skeptics, questions the link.[81] A 2014 meta analysis whichfollowed over 500,000 patients, concluded there is insufficient evidence to support the recommendation of high consumption ofpolyunsaturated fatty acids and low consumption of total saturated fats for cardiovascular health.[82]

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Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, but somestudies suggest a link with depression, cancer, and cerebral hemorrhage. In general, the low cholesterol levels seem to be a consequence, ratherthan a cause, of an underlying illness.[58] A genetic defect in cholesterol synthesis causes Smith­Lemli­Opitz syndrome, which is oftenassociated with low plasma cholesterol levels. Hyperthyroidism, or any other endocrine disturbance which causes upregulation of the LDLreceptor may result in hypocholesterolaemia.[83]

Cholesterol testing

The American Heart Association recommends testing cholesterol every five years for people aged 20 years or older.[84] A separate set ofAmerican Heart Association guidelines issued in 2013 indicates that patients taking statin medications should have their cholesterol tested 4–12 weeks after their first dose and then every 3–12 months thereafter.[85]

A blood sample after 12­hour fasting is taken by a doctor, or a home cholesterol­monitoring device is used to determine a lipoprotein profile.This measures total cholesterol, LDL (bad) cholesterol, HDL (good) cholesterol, and triglycerides. It is recommended to test cholesterol atleast every five years if a person has total cholesterol of 5.2 mmol/L or more (200+ mg/dL), or if a man over age 45 or a woman over age 50has HDL (good) cholesterol less than 1 mmol/L (40 mg/dL), or there are other risk factors for heart disease and stroke. Other risk factors forheart disease include Diabetes, Hypertension (or use of anti­hypertensive medications), low HDL, family history of CAD andhypercholesterolemia, and cigarette smoking.[86]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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

1. The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430" (http://www.wikipathways.org/index.php/Pathway:WP430).

Cholesteric liquid crystals

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

Stereoisomers

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Cholesterol has 256 stereoisomers that arise from its 8 stereocenters, although only two of the stereoisomers are of biochemical significance(nat­cholesterol and ent­cholesterol, for natural and enantiomer, respectively),[87][88] and only one occurs naturally (nat­cholesterol).

See also

Arcus senilis "Cholesterol ring" in the eyesCholesterol embolismCholesterol total synthesisDiet and heart diseaseFamilial hypercholesterolaemiaList of cholesterol in foodsNiemann–Pick disease Type COxycholesterolVertical Auto Profile

Additional images

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Steroidogenesis, usingcholesterol as buildingmaterial

Space­filling model ofthe Cholesterolmolecule

Numbering of thesteroid nuclei

References1. "Substance Data for 57­88­5".2. "Safety (MSDS) data for cholesterol" (http://physchem.ox.ac.uk/MSDS/CH/cholesterol.html). Retrieved 2007­10­20.3. http://www.pnas.org/content/70/8/2313.full.pdf4. Cholesterol (https://www.nlm.nih.gov/cgi/mesh/2013/MB_cgi?mode=&term=Cholesterol) at the US National Library of Medicine Medical Subject

Headings (MeSH)5. Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis.". J Steroid Biochem MolBiol 43 (8): 779–804. doi:10.1016/0960­0760(92)90307­5 (https://dx.doi.org/10.1016%2F0960­0760%2892%2990307­5). PMID 22217824(https://www.ncbi.nlm.nih.gov/pubmed/22217824).

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7. Chevreul (1816) "Recherches chimiques sur les corps gras, et particulièrement sur leurs combinaisons avec les alcalis. Sixième mémoire. Examen desgraisses d'homme, de mouton, de boeuf, de jaguar et d'oie" (Chemical researches on fatty substances, and particularly on their combinations o filipposine kapios with alkalis. Sixth memoir. Study of human, sheep, beef, jaguar and goose fat), Annales de Chimie et de Physique, 2 : 339­372. From page346 (http://books.google.com/books?id=DHCz1nhhYL8C&pg=PA346#v=onepage&q&f=false) : "Je nommerai cholesterine, de χολη, bile, et στερεος,solide, la substance cristallisée des calculs biliares humains, ... " (I will name cholesterine — from χολη (bile) and στερεος (solid) — the crystalizedsubstance from human gallstones ... )

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External links

GMD MS Spectrum (http://gmd.mpimp­golm.mpg.de/Spectrums/EC32F379­6956­4750­B41A­F063F3DD480E.aspx)Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (http://www.nhlbi.nih.gov/guidelines/cholesterol/) USNational Institutes of Health Adult Treatment Panel IIIAmerican Heart Association (http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/About­Cholesterol_UCM_001220_Article.jsp) – "About Cholesterol"Cholesterol at Lab Tests Online (http://labtestsonline.org/understanding/analytes/cholesterol/tab/test)Cholestestrol (http://www.radcliffecardiology.com/prevention­risk/cholestestrol)

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glass: ability of its enantiomer also to elicit homeostatic responses" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460484). J. Biol. Chem. 287 (40):33897–904. doi:10.1074/jbc.M112.360537 (https://dx.doi.org/10.1074%2Fjbc.M112.360537). PMC 3460484(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460484). PMID 22869373 (https://www.ncbi.nlm.nih.gov/pubmed/22869373).