Difference between revisions of "Cholesterol" - New World Encyclopedia

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'''Cholesterol''' is a [[sterol]] (a combination [[steroid]] and [[alcohol]]), a [[lipid]] found in the [[cell membrane]]s of all [[human body|body]] tissues, and is transported in the [[blood plasma]] of all [[animal]]s. Trace amounts of cholesterol are also found in [[plant]] membranes.
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'''Cholesterol''' is an important [[sterol]] (a combination [[steroid]] and [[alcohol]]) and a neutral [[lipid]] that is a major constituent in the [[cell membrane]]s of [[animal]]s and serves as a precursor of important [[hormone]]s and other substances. Cholesterol is the principal sterol in all [[vertebrate]] cells (McGraw-Hill 2002); trace amounts also are found in plant membranes. The name cholesterol originates from the Greek ''chole-'' ([[bile]]) and ''stereos'' (solid), and the chemical suffix ''-ol'' for an alcohol, as researchers first identified cholesterol in solid form in [[gallstone]]s in 1784.
  
The name originates from the [[Greek language|Greek]] ''chole-'' ([[bile]]) and ''stereos'' (solid), and the [[chemical]] [[suffix]] ''-ol'' for an alcohol, as researchers first identified cholesterol in solid form in [[gallstone]]s in [[1784]].
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Although cholesterol has a poor public image as a result of its role in influencing cardiovascular illness in humans, it is required for cells to function correctly and has a variety of vital functions. Cholesterol is used in [[tissue]] repair, strengthening cell membranes and influencing their membrane fluidity, manufacturing bile salts, as a precursor to steroid hormones (including [[estrogen]], [[testosterone]], [[cortisone]]), and as the raw material for the production of [[vitamin D]] (Kent 2002; Blakemore and Jennett 2001).  
  
Most of the cholesterol is synthesized by the body and some has dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the [[liver]], [[spinal cord]], [[brain]], and [[atheroma]]ta (arterial plaques). Cholesterol plays a central role in many [[biochemistry|biochemical]] processes, but is best known for the association of [[cardiovascular disease]] with various [[lipoprotein]] cholesterol transport patterns and [[hypercholesterolemia|high levels of cholesterol]] in the blood. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of [[lipoprotein]], spherical particles which have an exterior composed mainly of water-soluble proteins.
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While cholesterol plays a central role in many [[biochemistry|biochemical]] processes, it perhaps is best known for the association of [[cardiovascular disease]] with various [[lipoprotein]] cholesterol transport patterns and high levels of cholesterol in the blood. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles that have an exterior composed mainly of water-soluble proteins. The level of cholesterol can influence development of atherosclerotic plaque. Deposits of these on the walls of blood vessels causes narrowing of arteries, particularly the coronary arteries, reducing flow rate. This can be very important since flow rate depends on the fourth power of the radius of the artery, such that a reduction of the radius by one half would result in reducing the flow rate to one sixteenth of the original value (Blakemore and Jennett 2001).  
  
In recent years, the term "bad cholesterol" has been used to refer to cholesterol contained in LDL ([[low-density lipoprotein]]) which, according to the [[lipid hypothesis]], is thought to have harmful actions, and "good cholesterol" to refer to cholesterol contained in HDL ([[high-density lipoprotein]]), thought to have beneficial actions.
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In recent years, the term "bad cholesterol" has been used to refer to cholesterol contained in LDL ([[low-density lipoprotein]]) which, according to the [[lipid hypothesis]], is thought to have harmful actions, while "good cholesterol" is used to refer to cholesterol contained in HDL ([[high-density lipoprotein]]), thought to have beneficial actions.
  
==Physiology==
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The deleterious impact of cholesterol can largely be ameliorated by personal responsibility&mdash;specifically, diet and exercise, such as regular exercise and reducing or eliminating foods high in fat or practicing a low glycemic diet. Cholesterol can come directly from the diet or via biosynthesis in the body. Dietary intake of cholesterol itself is not the key factor influencing levels of cholesterol in the blood, due to regulatory mechanisms, but rather consumption of saturated dietary fats.
===Function===
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{{toc}}
Cholesterol is required to build and maintain [[cell membrane]]s; it regulates membrane fluidity over a wider range of [[temperature]]s. The [[hydroxyl]] group on cholesterol interacts with the [[phosphate]] head of the membrane, while the bulky [[steroid]] and the [[hydrocarbon]] chain is embedded in the membrane. Some research indicates that cholesterol may act as an [[antioxidant]].<ref name=Smith1991>Smith LL. Another cholesterol hypothesis: cholesterol as antioxidant. ''Free Radic Biol Med'' 1991;11:47-61. PMID 1937129.</ref> Cholesterol also aids in the manufacture of [[bile]] (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of [[fat soluble vitamins]], including vitamins [[vitamin A|A]], [[vitamin D|D]], [[vitamin E|E]] and [[vitamin K|K]]. It is the major precursor for the synthesis of [[vitamin D]] and of the various [[steroid hormone]]s (which include [[cortisol]] and [[aldosterone]] in the [[adrenal gland]]s, and the sex hormones [[progesterone]], the various [[estrogen]]s, [[testosterone]], and derivatives).
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In their 1985 Nobel Prize lecture, Brown and Goldstein stated that cholesterol is the "most decorated" molecule in biology, with more than 13 Nobel awards made to those involved in study of the substance, adding that "the property that makes it so useful in cell membranes, namely its absolute isolubility in water, also makes it lethal" (Blakemore and Jennett 2001).
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==Sources==
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The two main sources of cholesterol in humans are dietary intake and synthesis in the [[liver]] from [[fat]]s, [[carbohydrate]]s, and [[protein]]s, although some is also manufactured elsewhere in the [[human body|body]], particularly in the [[adrenal gland]]s and reproductive organs. Cholesterol can exist free or as an esther in which a [[fatty acid]] is bound to the hydroxyl group by an ester bond (McGraw-Hill 2002). Cholesterol is more abundant in those animal tissues that can either synthesize more or have more abundant, densely-packed membranes; for example, the liver, [[spinal cord]], [[brain]], and [[atheroma]]ta (arterial plaques).  
  
Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms [[lipid rafts]] in the [[plasma membrane]]. It also reduces the permeability of the plasma membrane to [[hydrogen]] ions ([[proton]]s) and [[sodium ion]]s.<ref name=Haines2001>Haines, TH. Do sterols reduce proton and sodium leaks through lipid bilayers? ''Prog Lipid Res'' 2001:40:299 – 324. PMID 11412894.</ref>
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All food containing animal [[fat]]s contains cholesterol. Food not containing animal fats generally contains no cholesterol or negligible amounts. Major dietary sources of cholesterol include eggs, beef, and poultry (USDA 2005).
  
Cholesterol is essential for the structure and function of invaginated [[caveolae]] and clathrin-coated pits, including the caveolae-dependent [[endocytosis]] and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using [[methyl beta cyclodextrin]] (MβCD) to remove cholesterol from the plasma membrane.
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Plants have trace amounts of cholesterol, so even a [[vegan]] diet, which includes no animal foods, has traces of cholesterol. However, the amounts are very small. For example, to ingest the amount of cholesterol in one egg, one would need to drink about 9.6 liters (19.57 pounds) of pure peanut oil (AHA 2007; Behrman and Gopalan 2005). Plant products (e.g. [[flax seed]], [[peanut]]), also contain cholesterol-like compounds, [[phytosterols]], which are suggested to help lower [[serum]] cholesterol (Ostlune et al. 2003).
  
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==Physiology==
 
===Synthesis and intake===
 
===Synthesis and intake===
[[Image:HMG-CoA reductase pathway.png|280px|thumb|right|The HMG-CoA reductase pathway]] Cholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the [[endoplasmic reticulum]], or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by [[receptor (biochemistry)|receptor]]-mediated [[endocytosis]] in clathrin-coated pits, and then hydrolysed in lysosomes.
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Cholesterol is required in the membrane of [[mammal]]ian cells for normal cellular function. It is the principle sterol in [[animal]] tissues and the most common sterol of [[eukaryote]]s (McGraw-Hill 2002).
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Cholesterol is either synthesized in the [[endoplasmic reticulum]] of these cells, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by receptor-mediated [[endocytosis]] in clathrin-coated pits, and then hydrolysed in lysosomes.
  
Cholesterol is primarily synthesized from [[acetyl CoA]] through the [[HMG-CoA reductase pathway]] in many [[cell (biology)|cells]] and [[biological tissue|tissues]]. About 20 &ndash; 25% of total daily production (~1 [[gram|g]]/[[day]]) occurs in the [[liver]]; other sites of higher synthesis rates include the [[intestines]], [[adrenal gland]]s and [[reproductive organ]]s. For a person of about 150 pounds (68 kg), typical total body content is about 35 [[gram|g]], typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg. Of the cholesterol input to the intestines via bile production, 92-97% is reabsorbed in the intestines and recycled via [[enterohepatic circulation]].
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[[Image:HMG-CoA reductase pathway.png|280px|thumb|right|The HMG-CoA reductase pathway]]
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Cholesterol is primarily synthesized from [[acetyl CoA]] through the [[HMG-CoA reductase pathway]] in many [[cell (biology)|cells]] and [[tissues]]. About 20&ndash;25 percent of the total daily production (~1 [[gram|g]]/[[day]]) occurs in the [[liver]]; other sites of higher synthesis rates include the [[intestine]]s, [[adrenal gland]]s, and [[reproductive organ]]s. For a person of about 150 pounds (68 kg), the typical total body content is about 35 g, the typical daily internal production is about 1 g, and the typical daily dietary intake is 200 to 300 mg. Of the cholesterol input to the intestines via bile production, 92-97 percent is reabsorbed in the intestines and recycled via [[enterohepatic circulation]].
  
[[Konrad Bloch]] and [[Feodor Lynen]] shared the [[Nobel Prize in Physiology or Medicine]] in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and [[fatty acid]] metabolism.
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Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and [[fatty acid]] metabolism.
  
 
===Regulation===
 
===Regulation===
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the [[homeostasis|homeostatic]] mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while 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]] [[Sterol regulatory element binding protein|SREBP]] (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and [[Insig1]]. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the [[Golgi apparatus]], where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a [[transcription factor]] to bind to the [[Sterol regulatory element|SRE]] (sterol regulatory element) of a number of genes to stimulate their [[Transcription (genetics)|transcription]]. Among the genes transcribed are the [[LDL receptor]] and [[HMG-CoA reductase pathway|HMG-CoA reductase]]. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.<ref name=Anderson2003>{{cite journal |author=Anderson RG. |title=Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. |journal=Trends Cell Biol |volume=13 |pages=534 &ndash; 9 |year=2003 |pmid=14507481}}</ref>
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Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the [[homeostasis|homeostatic]] mechanisms involved are only partly understood.  
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A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. Thus, dietary intake of cholesterol is not the key factor on serum levels of cholesterol, which is shown to be tied to consumption of saturated dietary fat. (Exercise is also a major factor, with exercise correlated with reducing cholesterol levels).
  
A large part of this mechanism was clarified by Dr [[Michael S. Brown]] and Dr [[Joseph L. Goldstein]] in the 1970s. They received the [[Nobel Prize in Physiology or Medicine]] for their work in 1985.<ref name=Anderson2003/>
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The main regulatory mechanism for cholesterol biosyntheis is the sensing of intracellular cholesterol in the [[endoplasmic reticulum]] by the [[protein]] SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and [[Insig1]]. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the [[Golgi apparatus]], where SREBP is cleaved by S1P and S2P (site 1/2 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) of a number of genes to stimulate their transcription. Among the genes transcribed are the 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 (Anderson 2003).
  
The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter.<ref name=Ockene2004>{{cite journal |author=Ockene IS, Chiriboga DE, Stanek EJ 3rd, Harmatz MG, Nicolosi R, Saperia G, Well AD, Freedson P, Merriam PA, Reed G, Ma Y, Matthews CE, Hebert JR. |title=Seasonal variation in serum cholesterol levels: treatment implications and possible mechanisms. |journal=Arch Intern Med |volume=164 |pages=863 &ndash; 70 |year=2004 |pmid=15111372}}</ref>
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A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985 (Anderson 2003).
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The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60-years-old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter (Ockene et al. 2004).
  
 
===Excretion===
 
===Excretion===
 
Cholesterol is excreted from the [[liver]] in [[bile]] and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the [[gallbladder]], it crystallises and is the major constituent of most [[gallstone]]s, although [[lecithin]] and [[bilirubin]] gallstones also occur less frequently.
 
Cholesterol is excreted from the [[liver]] in [[bile]] and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the [[gallbladder]], it crystallises and is the major constituent of most [[gallstone]]s, although [[lecithin]] and [[bilirubin]] gallstones also occur less frequently.
  
===Body fluids===
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===Body fluids, LDL, and HDL===
Cholesterol is minimally soluble in [[water]]; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by [[lipoprotein]]s - protein "molecular-suitcases" that are water-soluble and carry cholesterol and [[triglyceride]]s internally. The [[apolipoprotein]]s forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.
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Cholesterol is minimally soluble in [[water]]; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by [[lipoprotein]]s&mdash;protein "molecular-suitcases" that are water-soluble and carry cholesterol and [[triglyceride]]s internally. The [[apolipoprotein]]s forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.
  
The largest lipoproteins, which primarily transport fats from the [[intestine|intestinal]] [[mucosa]] to the liver, are called [[chylomicron]]s. They carry mostly fats in the form of [[triglyceride]]s and cholesterol. In the [[liver]], chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to [[low-density lipoprotein]] (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of [[atheroma]]tous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol".
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The largest lipoproteins, which primarily transport [[fat]]s from the [[intestine|intestinal]] [[mucosa]] to the liver, are called chylomicrons. They carry mostly fats in the form of [[triglyceride]]s and cholesterol.  
  
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.
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In the [[liver]], chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to [[low-density lipoprotein]] (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of [[atheroma]]tous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol."
  
[[High-density lipoprotein]] (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with [[atheroma]]tous disease progression within the arteries.
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The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be less than 200 mg/dl for normal blood cholesterol. Between 200 and 239 mg/dl is considered borderline-high, and over 240 mg/dl is considered high cholesterol.
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[[High-density lipoprotein]] (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol." In contrast, having small amounts of large HDL particles is independently associated with [[atheroma]]tous disease progression within the arteries.
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==Function==
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[[Image:Steroidogenesis.gif|thumb|240px|right|Cholesterol serves as a precursor for many important hormones]]
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Cholesterol is required to build and maintain [[cell membrane]]s; it regulates membrane fluidity over a wider range of [[temperature]]s. The [[hydroxyl]] group on cholesterol interacts with the [[phosphate]] head of the membrane, while the bulky [[steroid]] and the [[hydrocarbon]] chain is embedded in the membrane. In vertebrates, the highest concentration of cholesterol is in the myelin sheath that surrounds nerves and the in the plasma membrane that surrounds all cells (McGraw-Hill 2002).
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Cholesterol is important in the production and metabolism of other vital substances. It aids in the manufacture of [[bile]] (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins [[vitamin A|A]], [[vitamin D|D]], [[vitamin E|E]] and [[vitamin K|K]]. It is the major precursor for the synthesis of vitamin D, with the cholesterol in [[skin]] giving rise to 7-dehydrocholesterol, which is converted to vitamin D. It also is a major precursor of the various [[steroid hormone]]s (which include [[cortisol]] and [[aldosterone]] in the [[adrenal gland]]s, and the sex hormones [[progesterone]], the various [[estrogen]]s, [[testosterone]], and derivatives).
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Some research indicates that cholesterol may act as an [[antioxidant]] (Smith 1991).
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Recently, cholesterol has also been implicated in cell signaling processes, where it has been suggested that it forms lipid rafts in the [[plasma membrane]]. It also reduces the permeability of the plasma membrane to [[hydrogen]] ions ([[proton]]s) and [[sodium ion]]s (Haines 2001).
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Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the [[liquid crystal]]line ''cholesteric phase''. The cholesteric phase is in fact a [[chirality (chemistry)|chiral]] [[nematic phase]], and changes color when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive [[dye]]s, in liquid crystal [[thermometer]]s, and temperature-sensitive paints.
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Cholesterol is essential for the structure and function of invaginated [[caveolae]] and clathrin-coated pits, including the caveolae-dependent [[endocytosis]] and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using [[methyl beta cyclodextrin]] (MβCD) to remove cholesterol from the plasma membrane.
  
 
==Clinical significance==
 
==Clinical significance==
 
===Hypercholesterolemia===
 
===Hypercholesterolemia===
:''Main article: [[Hypercholesterolemia]]''
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[[Image:Cholesterol_Spacefill.jpeg|thumb|240px|right|Space-filling model of the cholesterol molecule]]
 
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Conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, are associated with [[atheroma]] formation in the walls of [[artery|arteries]], a condition known as ''[[atherosclerosis]]''. Atherosclerosis 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 [[inflammation|inflammatory]] mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.
Conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, are associated with [[atheroma]] formation in the walls of [[artery|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.
 
 
 
Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as ''atherogenic'' (prone to cause atherosclerosis).{{fact|date=March 2007}} Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. 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 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.{{Fact|date=February 2007}}
 
  
These effects are further complicated by the relative concentration of [[asymmetric dimethylarginine]] (ADMA) in the [[endothelium]], since ADMA down-regulates production of [[nitric oxide]], a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for cardiovascular disease.{{Fact|date=February 2007}}
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Elevated levels of the lipoprotein fractions, LDL, IDL, and VLDL are regarded as ''atherogenic'' (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. 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 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.  
  
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; however, ''no'' statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in ''asymptomatic'' people, i.e., no [[heart disease]], no history of heart attack, etc.{{Fact|date=March 2007}}
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These effects are further complicated by the relative concentration of [[asymmetric dimethylarginine]] (ADMA) in the [[endothelium]], since ADMA down-regulates production of [[nitric oxide]], a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for cardiovascular disease.
  
A follow-up from the [[Framingham Heart Study]] found that under age 50, cholesterol levels are directly correlated with 30-year overall and CVD mortality — overall death increases 5% and CVD death 9% for each 10 mg/dL increase in cholesterol. The same study also found an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age — an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. However, the authors attribute that inverse correlation to terminal subjects with diseases that affected cholestorol levels.<ref name=Anderson1987>{{cite journal |author=Anderson KM., Castelli WP, Levy D. |title=Cholesterol and mortality. 30 years of follow-up from the Framingham study. |journal=JAMA |volume=257 |pages=2176 &ndash; 80 |year=1987 |pmid=3560398}}</ref>
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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; however, ''no'' statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in ''asymptomatic'' people (i.e., no [[heart disease]], no history of heart attack, and so forth).  
  
Some of the better-designed recent randomized human outcome trials studying patients with coronary artery disease or its risk equivalents include the [[Heart Protection Study]] (HPS), the PROVE-IT trial, and the TNT trial. In addition, there are trials that have looked at the effect of lowering LDL as well as raising HDL and atheroma burden using [[intravascular ultrasound]]. Small trials have shown prevention of progression of coronary artery disease and possibly a slight reduction in atheroma burden with successful treatment of an abnormal lipid profile.
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A follow-up from the Framingham Heart Study found that under age 50, cholesterol levels are directly correlated with 30-year overall and CVD mortality&mdash;overall death increases five percent and CVD death nine percent for each 10 mg/dL increase in cholesterol. The same study also found an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age&mdash;an 11 percent increase overall and 14 percent increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. However, the authors attribute that inverse correlation to terminal subjects with diseases that affected cholestorol levels (Anderson et al. 1987).  
  
The [[American Heart Association]] provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:<ref name=AHA>[http://www.americanheart.org/cholesterol/about.jsp "About cholesterol"] - American Heart Association</ref>
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The [[American Heart Association]] provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease (AHA 2007):
  
 
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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 [[Mole (unit)|mmol]]/[[Litre|L]]){{Fact|date=April 2007}} , although a newer target of <70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL &mdash; another useful measure &mdash; 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.
+
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), although a newer target of <70 mg/dL can be considered in higher risk individuals based on some trials. A ratio of total cholesterol to HDL&mdash;another useful measure&mdash;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.
  
Patients should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] &minus; [total HDL] &minus; 20% of the [[triglyceride]] value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the Total, HDL, and Triglycerides are actually measured. The VLDL is estimated as one-fifth of the Triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake.
+
Patients should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] minus [total HDL] minus 20 percent of the [[triglyceride]] value equals estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the Total, HDL, and Triglycerides are actually measured. The VLDL is estimated as one-fifth of the Triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake.
  
Increasing clinical evidence{{Fact|date=February 2007}} has strongly supported the greater predictive value of more-sophisticated testing that directly measures both LDL and HDL particle concentrations and size, as opposed to the more usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration.
+
Increasing clinical evidence has strongly supported the greater predictive value of more-sophisticated testing that directly measures both LDL and HDL particle concentrations and size, as opposed to the more usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration.
 +
 
 +
Longe (2005) concludes that the most beneficial means to control cholesterol levels in probably a healthy diet and regular exercise. Key is reducing or eliminating foods high in animal fat. Among those diets recommended are the vegetarian diet, the Asian diet (with brown [[rice]] as the staple), and the low glycemic or diabetic diet (which can raise the HDL level by as much as 20 percent in three weeks). Low glycemic foods promote a slow but steady rise in blood sugar levels following a meal, which increases the level of HDL, and lower total cholesterol and triglycerides. Allowable foods for these diets are whole grain foods, leafy vegetables, certain fruit, legumes, fish, among others.
  
 
===Hypocholesterolemia===
 
===Hypocholesterolemia===
Abnormally low levels of cholesterol are termed ''[[hypocholesterolemia]]''. Research into the causes of this state is relatively limited, and while some studies suggest a link with [[depression (mood)|depression]], [[cancer]] and [[cerebral hemorrhage]] it is unclear whether the low cholesterol levels are a cause for these conditions or an [[epiphenomenon]][http://www.americanheart.org/presenter.jhtml?identifier=1208].
+
Abnormally low levels of cholesterol are termed ''[[hypocholesterolemia]]''. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, [[cancer]] and [[cerebral hemorrhage]] it is unclear whether the low cholesterol levels are a cause for these conditions or an [[epiphenomenon]] (Criqui 1994).
  
==Food sources==
+
==References==
Cholesterol is found in animal fats: all food containing animal fats contains cholesterol; food not containing animal fats either contains no cholesterol or negligible amounts. Major dietary sources of cholesterol include eggs, beef and poultry.<ref>[http://www.health.gov/dietaryguidelines/dga2005/report/HTML/table_e18.htm Nutrition and Your Health: Dietary Guidelines for Americans. Table E-18. Dietary Sources of Cholesterol Listed in Decreasing Order.]</ref>
+
* American Heart Association (AHA). 2007. [http://www.americanheart.org/cholesterol/about.jsp About cholesterol]. ''American Heart Association''. Retrieved July 3, 2007.
 
+
* Anderson, K. M., W. P. Castelli, and d. Levy. 1987. Cholesterol and mortality. 30 years of follow-up from the Framingham study. ''JAMA'' 257: 2176-2180. pmid 3560398.
Plants have trace amounts of cholesterol, so even a [[vegan]] diet, which includes no animal foods, has traces of cholesterol. However, the amounts are very small. For example, to ingest the amount of cholesterol in one egg, one would need to drink about 9.6 litres (19.57 pounds) of pure peanut oil.<ref name=AHA>[http://www.americanheart.org/cholesterol/about.jsp "About cholesterol"] - American Heart Association</ref> <ref name=behrman2005>Behrman EJ, Gopalan V. Cholesterol and plants. ''J Chem Educ'' 2005;82:1791-1793. [http://jchemed.chem.wisc.edu/HS/Journal/Issues/2005/Dec/clicSubscriber/V82N12/p1791.pdf PDF]</ref>
+
* Anderson, R. G. 2003. Joe Goldstein and Mike Brown: From cholesterol homeostasis to new paradigms in membrane biology. ''Trends Cell Biol'' 13: 534-539. pmid 14507481.
 
+
* Behrman, E. J., and V. Gopalan. 2005. Cholesterol and plants. ''J Chem Educ'' 82: 1791-1793.
Plant products (e.g. [[flax seed]], [[peanut]]), also contain cholesterol-like compounds, [[phytosterols]], which are suggested to help lower [[serum]] cholesterol.<ref name=ostlund2003>{{cite journal | author=Ostlund RE, Racette, SB, and Stenson WF | title=Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ | journal=Am J Clin Nutr | year=2003 | pages=1385-1589 | volume=77 | issue=6 |pmid=12791614}}</ref>
+
* Blakemore, C., and S. Jennett. 2001. ''The Oxford Companion to the Body''. New York: Oxford University Press. ISBN 019852403X.
 
+
* Criqui, M. H. 1994. [http://www.americanheart.org/presenter.jhtml?identifier=1208 Very low cholesterol and cholesterol lowering]. ''American Heart Association Task Force on Cholesterol Issues''. Retrieved July 3, 2007.
==Cholesteric liquid crystals==
+
* Haines, T. H. 2001. Do sterols reduce proton and sodium leaks through lipid bilayers? ''Prog Lipid Res'' 40: 299–324. PMID 11412894.
Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the [[liquid crystal]]line ''cholesteric phase''. The cholesteric phase is in fact a [[chirality (chemistry)|chiral]] [[nematic phase]], and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive [[dye]]s, in liquid crystal [[thermometer]]s and temperature-sensitive paints.
+
* Kent, M. 2002. ''Food and Fitness: A Dictionary of Diet and Exercise''. Oxford reference online. Oxford: Oxford University Press. ISBN 0198631472.
 
+
* Longe, J. L. 2005. ''The Gale Encyclopedia of Alternative Medicine''. Farmington Hills, Mich: Thomson/Gale. ISBN 0787693960.
==See also==
+
* McGraw-Hill. 2002. ''McGraw-Hill Encyclopedia of Science and Technology''. New York: McGraw-Hill. ISBN 0079136656.
* [[Triglyceride]]s
+
* Ockene, I. S., D. E. Chiriboga, E. J. Stanek, M. G. Harmatz, R. Nicolosi, G. Saperia, A. D. Well, P. Freedson, P. A. Merriam, G. Reed, Y. Ma, C. E. Matthews, and J. R. Hebert. 2004. Seasonal variation in serum cholesterol levels: Treatment implications and possible mechanisms. ''Arch Intern Med'' 164: 863-870. PMID 15111372.
* [[The International Network of Cholesterol Skeptics]]
+
* Ostlund, R. E., S. B. Racette, and W. F. Stenson. 2003. Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ. ''Am J Clin Nutr'' 77(6): 1385-1589. PMID 12791614.
* [[Diet and heart disease]]
+
* Smith, L. L. 1991. Another cholesterol hypothesis: Cholesterol as antioxidant. ''Free Radic Biol Med'' 11: 47-61. PMID 1937129.
 
+
* United States Department of Agriculture (USDA). 2005.[http://www.health.gov/dietaryguidelines/dga2005/report/HTML/table_e18.htm Nutrition and your health: Dietary guidelines for Americans. Table E-18. Dietary sources of cholesterol listed in decreasing order.] ''USDA''. Retrieved July 3, 2007.  
==Additional images==
 
<gallery>
 
Image:Steroidogenesis.gif|[[Steroidogenesis]]
 
Image:Cholesterol_Spacefill.jpeg|[[Space-filling model]] of the Cholesterol molecule
 
</gallery>
 
  
 
==External links==
 
==External links==
* [http://www.nhlbi.nih.gov/guidelines/cholesterol/ Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults ] US National Institutes of Health Adult Treatment Panel III
+
All links retrieved February 16, 2017.
* [http://www.fao.org/docrep/V4700E/V4700E08.htm Aspects of fat digestion and metabolism - UN/WHO Report 1994]
 
* [http://www.americanheart.org/cholesterol/about.jsp American Heart Association] - "About Cholesterol"
 
* [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~YwnjxU:1:FULL Hazardous Substances Data Bank - Cholesterol]
 
{{ChemicalSources}}
 
 
 
==References==
 
<references/>
 
  
 +
* [http://www.fao.org/docrep/V4700E/V4700E08.htm Aspects of fat digestion and metabolism - UN/WHO Report 1994].
  
 
{{credit|139067163}}
 
{{credit|139067163}}
 
 
  
 
[[Category:Life sciences]]
 
[[Category:Life sciences]]
 +
[[Category:Biochemistry]]

Revision as of 23:05, 16 February 2017

Cholesterol
Cholesterol
Cholesterol-3d.png
Chemical name 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
Chemical formula C27H46O
Molecular mass 386.65 g/mol
CAS number [57-88-5]
Density and phase 1.067 g/cm³, solid
Melting point 146-147 °C
Boiling point 360 °C (decomposes)
Solubility in water 0.095 mg/l (30 °C)
SMILES (C)CCC[C@@H](C)[C@H]1CC
[C@H]2[C@@H]3CC=C4C[C@@H]
(O)CC[C@]4(C)[C@H]3CC[C@]12C
Disclaimer and references

Cholesterol is an important sterol (a combination steroid and alcohol) and a neutral lipid that is a major constituent in the cell membranes of animals and serves as a precursor of important hormones and other substances. Cholesterol is the principal sterol in all vertebrate cells (McGraw-Hill 2002); trace amounts also are found in plant membranes. The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones in 1784.

Although cholesterol has a poor public image as a result of its role in influencing cardiovascular illness in humans, it is required for cells to function correctly and has a variety of vital functions. Cholesterol is used in tissue repair, strengthening cell membranes and influencing their membrane fluidity, manufacturing bile salts, as a precursor to steroid hormones (including estrogen, testosterone, cortisone), and as the raw material for the production of vitamin D (Kent 2002; Blakemore and Jennett 2001).

While cholesterol plays a central role in many biochemical processes, it perhaps is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles that have an exterior composed mainly of water-soluble proteins. The level of cholesterol can influence development of atherosclerotic plaque. Deposits of these on the walls of blood vessels causes narrowing of arteries, particularly the coronary arteries, reducing flow rate. This can be very important since flow rate depends on the fourth power of the radius of the artery, such that a reduction of the radius by one half would result in reducing the flow rate to one sixteenth of the original value (Blakemore and Jennett 2001).

In recent years, the term "bad cholesterol" has been used to refer to cholesterol contained in LDL (low-density lipoprotein) which, according to the lipid hypothesis, is thought to have harmful actions, while "good cholesterol" is used to refer to cholesterol contained in HDL (high-density lipoprotein), thought to have beneficial actions.

The deleterious impact of cholesterol can largely be ameliorated by personal responsibility—specifically, diet and exercise, such as regular exercise and reducing or eliminating foods high in fat or practicing a low glycemic diet. Cholesterol can come directly from the diet or via biosynthesis in the body. Dietary intake of cholesterol itself is not the key factor influencing levels of cholesterol in the blood, due to regulatory mechanisms, but rather consumption of saturated dietary fats.

In their 1985 Nobel Prize lecture, Brown and Goldstein stated that cholesterol is the "most decorated" molecule in biology, with more than 13 Nobel awards made to those involved in study of the substance, adding that "the property that makes it so useful in cell membranes, namely its absolute isolubility in water, also makes it lethal" (Blakemore and Jennett 2001).

Sources

The two main sources of cholesterol in humans are dietary intake and synthesis in the liver from fats, carbohydrates, and proteins, although some is also manufactured elsewhere in the body, particularly in the adrenal glands and reproductive organs. Cholesterol can exist free or as an esther in which a fatty acid is bound to the hydroxyl group by an ester bond (McGraw-Hill 2002). Cholesterol is more abundant in those animal tissues that can either synthesize more or have more abundant, densely-packed membranes; for example, the liver, spinal cord, brain, and atheromata (arterial plaques).

All food containing animal fats contains cholesterol. Food not containing animal fats generally contains no cholesterol or negligible amounts. Major dietary sources of cholesterol include eggs, beef, and poultry (USDA 2005).

Plants have trace amounts of cholesterol, so even a vegan diet, which includes no animal foods, has traces of cholesterol. However, the amounts are very small. For example, to ingest the amount of cholesterol in one egg, one would need to drink about 9.6 liters (19.57 pounds) of pure peanut oil (AHA 2007; Behrman and Gopalan 2005). Plant products (e.g. flax seed, peanut), also contain cholesterol-like compounds, phytosterols, which are suggested to help lower serum cholesterol (Ostlune et al. 2003).

Physiology

Synthesis and intake

Cholesterol is required in the membrane of mammalian cells for normal cellular function. It is the principle sterol in animal tissues and the most common sterol of eukaryotes (McGraw-Hill 2002).

Cholesterol is either synthesized in the endoplasmic reticulum of these cells, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes.

The HMG-CoA reductase pathway

Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20–25 percent of the total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands, and reproductive organs. For a person of about 150 pounds (68 kg), the typical total body content is about 35 g, the typical daily internal production is about 1 g, and the typical daily dietary intake is 200 to 300 mg. Of the cholesterol input to the intestines via bile production, 92-97 percent is reabsorbed in the intestines and recycled via enterohepatic circulation.

Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism.

Regulation

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, while lower intake from food has the opposite effect. Thus, dietary intake of cholesterol is not the key factor on serum levels of cholesterol, which is shown to be tied to consumption of saturated dietary fat. (Exercise is also a major factor, with exercise correlated with reducing cholesterol levels).

The main regulatory mechanism for cholesterol biosyntheis is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 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) of a number of genes to stimulate their transcription. Among the genes transcribed are the 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 (Anderson 2003).

A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985 (Anderson 2003).

The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60-years-old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter (Ockene et al. 2004).

Excretion

Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.

Body fluids, LDL, and HDL

Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins—protein "molecular-suitcases" that are water-soluble and carry cholesterol and triglycerides internally. The apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.

The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly fats in the form of triglycerides and cholesterol.

In the liver, chylomicron particles release triglycerides and some cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to low-density lipoprotein (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol."

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be less than 200 mg/dl for normal blood cholesterol. Between 200 and 239 mg/dl is considered borderline-high, and over 240 mg/dl is considered high cholesterol.

High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol." In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Function

Cholesterol serves as a precursor for many important hormones

Cholesterol is required to build and maintain cell membranes; it regulates membrane fluidity over a wider range of temperatures. The hydroxyl group on cholesterol interacts with the phosphate head of the membrane, while the bulky steroid and the hydrocarbon chain is embedded in the membrane. In vertebrates, the highest concentration of cholesterol is in the myelin sheath that surrounds nerves and the in the plasma membrane that surrounds all cells (McGraw-Hill 2002).

Cholesterol is important in the production and metabolism of other vital substances. It aids in the manufacture of bile (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D, with the cholesterol in skin giving rise to 7-dehydrocholesterol, which is converted to vitamin D. It also is a major precursor of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterone, and derivatives).

Some research indicates that cholesterol may act as an antioxidant (Smith 1991).

Recently, cholesterol has also been implicated in cell signaling processes, where it has been suggested that it forms lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions (Haines 2001).

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 color when its temperature changes. Therefore, cholesterol derivatives are commonly used as temperature-sensitive dyes, in liquid crystal thermometers, and temperature-sensitive paints.

Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including the caveolae-dependent endocytosis and clathrin-dependent endocytosis. The role of cholesterol in caveolae-dependent and clathrin-dependent endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane.

Clinical significance

Hypercholesterolemia

Space-filling model of the cholesterol molecule

Conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis. Atherosclerosis 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.

Elevated levels of the lipoprotein fractions, LDL, IDL, and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. 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 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.

These effects are further complicated by the relative concentration of asymmetric dimethylarginine (ADMA) in the endothelium, since ADMA down-regulates production of nitric oxide, a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for cardiovascular disease.

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; however, no statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in asymptomatic people (i.e., no heart disease, no history of heart attack, and so forth).

A follow-up from the Framingham Heart Study found that under age 50, cholesterol levels are directly correlated with 30-year overall and CVD mortality—overall death increases five percent and CVD death nine percent for each 10 mg/dL increase in cholesterol. The same study also found an inverse correlation between cholesterol levels and mortality in subjects over 50 years of age—an 11 percent increase overall and 14 percent increase in CVD mortality per 1 mg/dL per year drop in cholesterol levels. However, the authors attribute that inverse correlation to terminal subjects with diseases that affected cholestorol levels (Anderson et al. 1987).

The American Heart Association provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease (AHA 2007):

Level mg/dL Level mmol/L Interpretation
<200 <5.2 Desirable level corresponding to lower risk for heart disease
200-239 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), although a newer target of <70 mg/dL can be considered in higher risk individuals based on some 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.

Patients should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] minus [total HDL] minus 20 percent of the triglyceride value equals estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the Total, HDL, and Triglycerides are actually measured. The VLDL is estimated as one-fifth of the Triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake.

Increasing clinical evidence has strongly supported the greater predictive value of more-sophisticated testing that directly measures both LDL and HDL particle concentrations and size, as opposed to the more usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration.

Longe (2005) concludes that the most beneficial means to control cholesterol levels in probably a healthy diet and regular exercise. Key is reducing or eliminating foods high in animal fat. Among those diets recommended are the vegetarian diet, the Asian diet (with brown rice as the staple), and the low glycemic or diabetic diet (which can raise the HDL level by as much as 20 percent in three weeks). Low glycemic foods promote a slow but steady rise in blood sugar levels following a meal, which increases the level of HDL, and lower total cholesterol and triglycerides. Allowable foods for these diets are whole grain foods, leafy vegetables, certain fruit, legumes, fish, among others.

Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, cancer and cerebral hemorrhage it is unclear whether the low cholesterol levels are a cause for these conditions or an epiphenomenon (Criqui 1994).

References
ISBN links support NWE through referral fees

  • American Heart Association (AHA). 2007. About cholesterol. American Heart Association. Retrieved July 3, 2007.
  • Anderson, K. M., W. P. Castelli, and d. Levy. 1987. Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA 257: 2176-2180. pmid 3560398.
  • Anderson, R. G. 2003. Joe Goldstein and Mike Brown: From cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol 13: 534-539. pmid 14507481.
  • Behrman, E. J., and V. Gopalan. 2005. Cholesterol and plants. J Chem Educ 82: 1791-1793.
  • Blakemore, C., and S. Jennett. 2001. The Oxford Companion to the Body. New York: Oxford University Press. ISBN 019852403X.
  • Criqui, M. H. 1994. Very low cholesterol and cholesterol lowering. American Heart Association Task Force on Cholesterol Issues. Retrieved July 3, 2007.
  • Haines, T. H. 2001. Do sterols reduce proton and sodium leaks through lipid bilayers? Prog Lipid Res 40: 299–324. PMID 11412894.
  • Kent, M. 2002. Food and Fitness: A Dictionary of Diet and Exercise. Oxford reference online. Oxford: Oxford University Press. ISBN 0198631472.
  • Longe, J. L. 2005. The Gale Encyclopedia of Alternative Medicine. Farmington Hills, Mich: Thomson/Gale. ISBN 0787693960.
  • McGraw-Hill. 2002. McGraw-Hill Encyclopedia of Science and Technology. New York: McGraw-Hill. ISBN 0079136656.
  • Ockene, I. S., D. E. Chiriboga, E. J. Stanek, M. G. Harmatz, R. Nicolosi, G. Saperia, A. D. Well, P. Freedson, P. A. Merriam, G. Reed, Y. Ma, C. E. Matthews, and J. R. Hebert. 2004. Seasonal variation in serum cholesterol levels: Treatment implications and possible mechanisms. Arch Intern Med 164: 863-870. PMID 15111372.
  • Ostlund, R. E., S. B. Racette, and W. F. Stenson. 2003. Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ. Am J Clin Nutr 77(6): 1385-1589. PMID 12791614.
  • Smith, L. L. 1991. Another cholesterol hypothesis: Cholesterol as antioxidant. Free Radic Biol Med 11: 47-61. PMID 1937129.
  • United States Department of Agriculture (USDA). 2005.Nutrition and your health: Dietary guidelines for Americans. Table E-18. Dietary sources of cholesterol listed in decreasing order. USDA. Retrieved July 3, 2007.

External links

All links retrieved February 16, 2017.

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