Cholesterol
Names | |
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IUPAC name
Cholest-5-en-3β-ol
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Systematic IUPAC name
(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-Dimethyl-1-[(2R)-6-methylheptan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[a]phenanthren-7-ol | |
Other names
Cholesterin, Cholesteryl alcohol[1]
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Identifiers | |
3D model (
JSmol ) |
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ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard
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100.000.321 |
IUPHAR/BPS |
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KEGG | |
PubChem CID
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UNII | |
CompTox Dashboard (EPA)
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Properties | |
C27H46O | |
Molar mass | 386.65 g/mol |
Appearance | white crystalline powder[2] |
Density | 1.052 g/cm3 |
Melting point | 148 to 150 °C (298 to 302 °F; 421 to 423 K)[2] |
Boiling point | 360 °C (680 °F; 633 K) (decomposes) |
0.095 mg/L (30 °C)[1] | |
Solubility | soluble in acetone, benzene, chloroform, ethanol, ether, hexane, isopropyl myristate, methanol |
-284.2·10−6 cm3/mol | |
Hazards | |
Flash point | 209.3 ±12.4 °C |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Types of fats in food |
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Components |
Manufactured fats |
Cholesterol is the principal
Cholesterol is
Elevated levels of cholesterol in the blood, especially when bound to low-density lipoprotein (LDL, often referred to as "bad cholesterol"), may increase the risk of cardiovascular disease.[8]
François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. In 1815, chemist Michel Eugène Chevreul named the compound "cholesterine".[9][10]
Etymology
The word cholesterol comes from
.Physiology
Cholesterol is essential for all animal life. While most cells are capable of synthesizing it, the majority of cholesterol is ingested or synthesized by hepatocytes and transported in the blood to peripheral cells. The levels of cholesterol in peripheral tissues is dictated by a balance of uptake and export.[11] Under normal conditions, brain cholesterol is separate from peripheral cholesterol, i.e., the dietary and hepatic cholesterol do not cross the blood brain barrier. Rather, astrocytes produce and distribute cholesterol in the brain.[12]
De novo synthesis, both in astrocytes and hepatocytes, occurs by a complex 37-step process. This begins with the
Typical daily cholesterol dietary intake for a man in the United States is 307 mg.
Plants make cholesterol in very small amounts.
Function
Membranes
Cholesterol is present in varying degrees in all animal
The structure of the tetracyclic ring of cholesterol contributes to the fluidity of the cell membrane, as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.[24] In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes,[25] hydrogen ions, and sodium ions.[26]
Substrate presentation
Cholesterol regulates the biological process of
Signaling
Cholesterol is also implicated in cell signaling processes, assisting in the formation of
Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor, GABAA receptor, and the inward-rectifier potassium channel.[30] Cholesterol also activates the estrogen-related receptor alpha (ERRα), and may be the endogenous ligand for the receptor.[31][32] The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body.[32] Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of the effects of statins and bisphosphonates on bone, muscle, and macrophages.[31][32] On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol.[31][32]
As a chemical precursor
Within cells, cholesterol is also a precursor molecule for several
Epidermis
The stratum corneum is the outermost layer of the epidermis.[34][35] It is composed of terminally differentiated and enucleated corneocytes that reside within a lipid matrix, like "bricks and mortar."[34][35] Together with ceramides and free fatty acids, cholesterol forms the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (≈50% by weight), cholesterol (≈25% by weight), and free fatty acids (≈15% by weight), with smaller quantities of other lipids also being present.[34][35] Cholesterol sulfate reaches its highest concentration in the granular layer of the epidermis. Steroid sulfate sulfatase then decreases its concentration in the stratum corneum, the outermost layer of the epidermis.[36] The relative abundance of cholesterol sulfate in the epidermis varies across different body sites with the heel of the foot having the lowest concentration.[35]
Metabolism
Cholesterol is recycled in the body. The liver excretes cholesterol into biliary fluids, which are then stored in the gallbladder, which then excretes them in a non-esterified form (via bile) into the digestive tract. Typically, about 50% of the excreted cholesterol is reabsorbed by the small intestine back into the bloodstream.
Biosynthesis and regulation
Biosynthesis
Almost all animal tissues synthesize cholesterol from
Synthesis within the body starts with the
This molecule is then reduced to
Mevalonate is finally converted to isopentenyl pyrophosphate (IPP) through two phosphorylation steps and one decarboxylation step that requires ATP.
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
Oxidosqualene cyclase then cyclizes squalene to form lanosterol.
Finally, lanosterol is converted to cholesterol via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway.[39][40][41][42][43] The final 19 steps to cholesterol contain
Regulation of cholesterol synthesis
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the
The cleaved SREBP then migrates to the nucleus and acts as a
Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain senses signals for its degradation. Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteasome. 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.[47]
Plasma transport and regulation of absorption
As an isolated molecule, cholesterol is only minimally soluble in
There are several types of lipoproteins in the blood. In order of increasing density, they are
Lipoprotein particles are organized by complex
Chylomicrons, the least dense cholesterol transport particles, contain
VLDL particles are produced by the liver from
LDL particles are the major blood cholesterol carriers. Each one contains approximately 1,500 molecules of cholesterol ester. LDL particle shells contain just one molecule of
LDL receptors are used up during cholesterol absorption, and its synthesis is regulated by
When this process becomes unregulated, LDL particles without receptors begin to appear in the blood. These LDL particles are oxidized and taken up by
HDL particles are thought to transport cholesterol back to the liver, either for excretion or for other tissues that synthesize hormones, in a process known as reverse cholesterol transport (RCT).[51] Large numbers of HDL particles correlates with better health outcomes,[52] whereas low numbers of HDL particles is associated with atheromatous disease progression in the arteries.[53]
Metabolism, recycling and excretion
Cholesterol is susceptible to oxidation and easily forms oxygenated derivatives called 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 they were shown to exert inhibitory actions on cholesterol biosynthesis.[54] 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.[55]
In biochemical experiments radiolabelled forms of cholesterol, such as tritiated-cholesterol are used. These derivatives undergo degradation upon storage and it is essential to purify cholesterol prior to use. Cholesterol can be purified using small Sephadex LH-20 columns.[56]
Cholesterol is oxidized by the liver into a variety of
Although cholesterol is a steroid generally associated with mammals, the human pathogen
Dietary sources
Plant cells synthesize cholesterol as a precursor for other compounds, such as
Medical guidelines and recommendations
In 2015, the scientific advisory panel of U.S. Department of Health and Human Services and U.S. Department of Agriculture for the 2015 iteration of the Dietary Guidelines for Americans dropped the previously recommended limit of consumption of dietary cholesterol to 300 mg per day with a new recommendation to "eat as little dietary cholesterol as possible" and acknowledging an association between a diet low in cholesterol and reduced risk of cardiovascular disease.[69]
A 2013 report by the American Heart Association and the American College of Cardiology recommended focusing on healthy dietary patterns rather than specific cholesterol limits, as they are hard for clinicians and consumers to implement. They recommend the
Some supplemental guidelines have recommended doses of phytosterols in the 1.6–3.0 grams per day range (Health Canada, EFSA, ATP III, FDA). A meta-analysis demonstrated a 12% reduction in LDL-cholesterol at a mean dose of 2.1 grams per day.[72] The benefits of a diet supplemented with phytosterols have also been questioned.[73]
Clinical significance
Hypercholesterolemia
According to the lipid hypothesis, elevated levels of cholesterol in the blood lead to atherosclerosis which may increase the risk of heart attack, stroke, and peripheral artery disease. Since higher blood LDL – especially higher LDL concentrations and smaller LDL particle size – contributes to this process more than the cholesterol content of the HDL particles,[8] LDL particles are often termed "bad cholesterol". High concentrations of functional HDL, which can remove cholesterol from cells and atheromas, offer protection and are commonly referred to as "good cholesterol". These balances are mostly genetically determined, but can be changed by body composition, medications, diet,[74] and other factors.[75] A 2007 study demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is larger in older people.[76]
Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis.[77] Conversely, 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 are high. 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".[78][79]
About one in 250 individuals can have a genetic mutation for the LDL cholesterol receptor that causes them to have familial hypercholesterolemia.[80] Inherited high cholesterol can also include genetic mutations in the PCSK9 gene and the gene for apolipoprotein B.[81]
Elevated cholesterol levels are treatable by a diet that reduces or eliminates saturated fat, trans fats, and high cholesterol foods,[82][83] often followed by one of various hypolipidemic agents, such as statins, fibrates, cholesterol absorption inhibitors, monoclonal antibody therapy (PCSK9 inhibitors), nicotinic acid derivatives or bile acid sequestrants.[84] There are several international guidelines on the treatment of hypercholesterolemia.[85]
Human trials using 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.[86] Studies have shown that reducing LDL cholesterol levels by about 38.7 mg/dL with the use of statins can reduce cardiovascular disease and stroke risk by about 21%.[87] Studies have also found that statins reduce atheroma progression.[88] As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels (total cholesterol below 5.0 mmol/L [193 mg/dL]),[89] and in men without cardiovascular disease, there is benefit from lowering abnormally high cholesterol levels ("primary prevention").[90] Primary prevention in women was originally practiced only by extension of the findings in studies on men,[91] since, in women, none of the large statin trials conducted prior to 2007 demonstrated a significant reduction in overall mortality or in cardiovascular endpoints.[92] Meta-analyses have demonstrated significant reductions in all-cause and cardiovascular mortality, without significant heterogeneity by sex.[93]
Level | Interpretation | |
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dL
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mmol/L | |
< 200 | < 5.2 | Desirable level (lower risk) |
200–240 | 5.2–6.2 | Borderline high risk |
> 240 | > 6.2 | High risk |
The 1987 report of
More current testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, allowing cholesterol analysis to be more nuanced. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L).[96][97]
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]. 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.[98]
In the Framingham Heart Study, each 10 mg/dL (0.6 mmol/L) increase in total cholesterol levels increased 30-year overall mortality by 5% and CVD mortality by 9%. While subjects over the age of 50 had an 11% increase in overall mortality, and a 14% increase in cardiovascular disease mortality per 1 mg/dL (0.06 mmol/L) year drop in total cholesterol levels. The researchers attributed this phenomenon to a different correlation, whereby the disease itself increases risk of death, as well as changes a myriad of factors, such as weight loss and the inability to eat, which lower serum cholesterol.[99] This effect was also shown in men of all ages and women over 50 in the Vorarlberg Health Monitoring and Promotion Programme. These groups were more likely to die of cancer, liver diseases, and mental diseases with very low total cholesterol, of 186 mg/dL (10.3 mmol/L) and lower. This result indicates the low-cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a marker for frailty occurring with age.[100]
Hypocholesterolemia
Abnormally low levels of cholesterol are termed
Testing
The American Heart Association recommends testing cholesterol every 4–6 years for people aged 20 years or older.[102] A separate set of American Heart Association guidelines issued in 2013 indicates that people taking statin medications should have their cholesterol tested 4–12 weeks after their first dose and then every 3–12 months thereafter.[103][104] For men ages 45 to 65 and women ages 55 to 65, a cholesterol test should occur every 1–2 years, and for seniors over age 65, an annual test should be performed.[103]
A blood sample after 12-hours of fasting is taken by a healthcare professional from an arm vein to measure a lipid profile for a) total cholesterol, b) HDL cholesterol, c) LDL cholesterol, and d) triglycerides.[3][103] Results may be expressed as "calculated", indicating a calculation of total cholesterol, HDL, and triglycerides.[3]
Cholesterol is tested to determine for "normal" or "desirable" levels if a person has a total cholesterol of 5.2 mmol/L or less (200 mg/dL), an HDL value of more than 1 mmol/L (40 mg/dL, "the higher, the better"), an LDL value of less than 2.6 mmol/L (100 mg/dL), and a triglycerides level of less than 1.7 mmol/L (150 mg/dL).
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
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 it changes colour when its temperature changes. This makes cholesterol derivatives useful for indicating temperature in liquid-crystal display thermometers and in temperature-sensitive paints.[citation needed]
Stereoisomers
Cholesterol has 256
Additional images
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Cholesterol units conversion
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Steroidogenesis, using cholesterol as building material
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Space-filling model of the Cholesterol molecule
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Numbering of the steroid nuclei
See also
- Arcus senilis "Cholesterol ring" in the eyes
- Cardiovascular disease
- Cholesterol embolism
- Cholesterol total synthesis
- Familial hypercholesterolemia
- Hypercholesterolemia "High Cholesterol"
- Hypocholesterolemia "Low Cholesterol"
- Janus-faced molecule
- List of cholesterol in foods
- Niemann–Pick disease Type C
- Oxycholesterol
- Remnant cholesterol
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Je nommerai cholesterine, de χολη, bile, et στερεος, solide, la substance cristallisée des calculs biliares humains, ...
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External links
- Media related to Cholesterol at Wikimedia Commons