Cholesterol is a waxy steroid A steroid is a type of organic compound that contains a specific arrangement of four rings that are joined to each other. Examples of steroids include cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone metabolite Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial microbiology. A secondary metabolite is not found in the cell membranes The cell membrane is one biological membrane separating the interior of a cell from the outside environment and transported in the blood plasma Blood plasma is the yellow liquid component of blood, in which the blood cells in whole blood would normally be suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid. It is mostly water and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon of all animals Animals are a major group of mostly multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and independently. All animals are also.^[2] It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step. Examples for such multi-step biosynthetic pathways are those for the of bile acids Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids conjugated to glycine or taurine. In humans, taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic acid, and chenodeoxycholic acid. Bile acids, glycine and taurine, steroid hormones Steroid hormones are steroids that act as hormones. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors, though technically sterols rather than, and fat-soluble vitamins including Vitamin A Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal. This molecule is absolutely necessary for both scotopic and color vision. In another version the vitamin is necessary for the function of the reproductive systems of both male and female mammals. Vitamin A also, Vitamin D Vitamin D is a group of fat-soluble secosteroids, the two major physiologically relevant forms of which are vitamin D2 and vitamin D3 (cholecalciferol). Vitamin D without a subscript refers to either D2 or D3 or both. Vitamin D3 is produced in the skin of vertebrates after exposure to ultraviolet B light from the sun or artificial sources, and, Vitamin E Vitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ- tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation. Of these, α-tocopherol (also written as alpha-tocopherol), and Vitamin K Vitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation, but also a number of other proteins that chelate calcium ion, and are involved in bone and other tissue metabolism. They are 2-methyl-1,4-naphthoquinone derivatives. Cholesterol is the principal sterol Sterols are an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol. Cholesterol is vital to cellular function, and a precursor to fat-soluble vitamins and steroid hormones synthesized by animals, but small quantities are synthesized in other eukaryotes A eukaryote is an organism whose cells contain complex structures enclosed within membranes. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear envelope, within which the genetic material is carried. The presence of a nucleus gives eukaryotes their name, which comes from the, such as plants Plants are living organisms belonging to the kingdom Plantae. They include familiar organisms such as trees, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The scientific study of plants, known as botany, has identified about 350,000 extant species of plants, defined as seed plants, bryophytes, ferns and fern allies. As of 2004, and fungi A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. The Fungi (pronounced /ˈfʌndʒaɪ/ or /ˈfʌŋɡaɪ/) are classified as a kingdom that is separate from plants, animals and bacteria. One major difference is that fungal cells have cell. It is almost completely absent among prokaryotes The prokaryotes are a group of organisms that lack a cell nucleus (= karyon), or any other membrane-bound organelles. They differ from the eukaryotes, which have a cell nucleus. Most are unicellular, but a few prokaryotes such as myxobacteria have multicellular stages in their life cycles. The word prokaryote comes from the Greek πρό- (pro-) &, which include bacteria.^[3] Although cholesterol is an important and necessary molecule for animals, a high level of serum cholesterol is an indicator for diseases such as heart disease Heart disease or cardiopathy is an umbrella term for a variety of different diseases affecting the heart. As of 2007, it is the leading cause of death in the United States, England, Canada and Wales, killing one person every 34 seconds in the United States alone.[verification needed].

The name cholesterol originates from the Greek Greek , an independent branch of the Indo-European family of languages, is the language of the Greeks. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. In its ancient form, it is the language of classical ancient Greek literature and the New Testament of chole- (bile Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum) and stereos (solid), and the chemical In chemistry, a chemical substance is a material with a specific chemical composition suffix In linguistics, a suffix is an affix which is placed after the stem of a word. Common examples are case endings, which indicate the grammatical case of nouns or adjectives, and verb endings, which form the conjugation of verbs. Particularly in the study of Semitic languages, a suffix is called an afformative, as they can alter the form of the -ol for an alcohol, as François Poulletier de la Salle first identified cholesterol in solid form in gallstones In medicine, gallstones are crystalline bodies formed within the body by accretion or concretion of normal or abnormal bile components, in 1769. However, it was only in 1815 that chemist Eugène Chevreul Michel Eugène Chevreul was a French chemist whose work with fatty acids led to early applications in the fields of art and science. He is credited with the discovery of margaric acid and designing an early form of soap made from animal fats and salt. He lived to 102 and was a pioneer in the field of gerontology named the compound "cholesterine".^[4]

Physiology

Overview

Since cholesterol is essential for all animal life, it is primarily synthesized from simpler substances within the body. However, high levels in blood circulation, depending on how it is transported within lipoproteins A lipoprotein is a biochemical assembly that contains both proteins and lipids whose function is to transport water-insoluble lipids in the water-based bloodstream. The lipids or their derivatives may be covalently or non-covalently bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins and toxins are, are strongly associated with progression of atherosclerosis Atherosclerosis is a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by low-density. For a person of about 68 kg (150 pounds), typical total body cholesterol synthesis is about 1 g (1,000 mg) per day, and total body content is about 35 g. Typical daily additional dietary intake, in the United States is 200–300 mg^{[citation needed]}. The body compensates for cholesterol intake by reducing the amount synthesized.

Cholesterol is recycled. It is excreted by the liver via the bile into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream. Phytosterols Phytosterols are a group of steroid alcohols, phytochemicals naturally occurring in plants. Phytosterols occur naturally in small quantities in vegetable oils, especially sea buckthorn oil (1640 mg/100g oil), corn oil (968 mg/100g), and soybean oil (327 mg/100g oil). One such phytosterol complex, isolated from vegetable oil, is cholestatin, can compete cholesterol reabsorption in intestinal tract back into the intestinal lumen for elimination.^[5]

Function

Cholesterol is required to build and maintain membranes The cell membrane is one biological membrane separating the interior of a cell from the outside environment; it regulates membrane fluidity over the range of physiological temperatures. The hydroxyl In chemistry, hydroxyl is a compound containing an oxygen atom bound covalently with a hydrogen atom. The neutral form of this group is a hydroxyl radical. The hydroxyl anion is called hydroxide; it is a diatomic ion with a single negative electronic charge. In discussions of synthetic methods in organic chemistry the hydroxyl group (–OH) is group on cholesterol interacts with the polar In chemistry, polarity refers to a separation of electric charge leading to a molecule having an electric dipole. Polar molecules can bond together due to dipole–dipole intermolecular forces between one molecule with asymmetrical charge distribution and another molecule also with asymmetrical charge distribution. Molecular polarity is dependent head groups of the membrane The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus and other sub-cellular structures. The lipid phospholipids Phospholipids are a class of lipids and are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from sphingosine instead of glycerol. The first phospholipid and sphingolipids Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine. These compounds play important roles in signal transmission and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue, while the bulky steroid A steroid is a type of organic compound that contains a specific arrangement of four rings that are joined to each other. Examples of steroids include cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone and the hydrocarbon In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls. Aromatic hydrocarbons , alkanes, alkenes, cycloalkanes and alkyne-based compounds are different types of hydrocarbons chain are embedded in the membrane, alongside the nonpolar In chemistry, polarity refers to a separation of electric charge leading to a molecule having an electric dipole. Polar molecules can bond together due to dipole–dipole intermolecular forces between one molecule with asymmetrical charge distribution and another molecule also with asymmetrical charge distribution. Molecular polarity is dependent fatty acid chain In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. The most occurring natural fatty acids have an even number of carbon atoms because their biosynthesis involves acetyl-CoA, a coenzyme carrying a two-carbon-atom group (see fatty acid synthesis) of the other lipids. In this structural role, cholesterol reduces the permeability of the plasma membrane to protons (positive hydrogen Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of 1.00794 u (1.007825 u for Hydrogen-1), hydrogen is the lightest and most abundant chemical element, constituting roughly 75 % of the Universe's elemental mass. Stars in the main sequence are mainly composed of hydrogen in its ions) and sodium ions Sodium is a metallic element with a symbol Na (from Latin natrium or Arabic natrun) and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1" (formerly known as ‘group IA’). It has only one stable isotope, 23Na.^[6]

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis Endocytosis is the process by which cells absorb molecules from outside the cell by engulfing them with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane. The process opposite to endocytosis is exocytosis. The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane The cell membrane is one biological membrane separating the interior of a cell from the outside environment. In many neurons, a myelin Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a glial cell. Schwann cells supply the myelin for peripheral neurons, whereas oligodendrocytes, specifically of the interfascicular type, sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell Schwann cells are glia of the peripheral nervous system . They are involved in many important aspects of peripheral nerve biology; the conduction of nervous impulses along axons, nerve development and regeneration, trophic support for neurons, production of the nerve extracellular matrix and presentation of antigens to T-lymphocytes. Charcot-Marie- membrane, provides insulation for more efficient conduction of impulses.^[7]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum, which is then stored in the gallbladder In vertebrates the gallbladder is a small organ that aids digestion and stores bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated. Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, Vitamin A Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal. This molecule is absolutely necessary for both scotopic and color vision. In another version the vitamin is necessary for the function of the reproductive systems of both male and female mammals. Vitamin A also, Vitamin D Vitamin D is a group of fat-soluble secosteroids, the two major physiologically relevant forms of which are vitamin D2 and vitamin D3 (cholecalciferol). Vitamin D without a subscript refers to either D2 or D3 or both. Vitamin D3 is produced in the skin of vertebrates after exposure to ultraviolet B light from the sun or artificial sources, and, Vitamin E Vitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ- tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation. Of these, α-tocopherol (also written as alpha-tocopherol), and Vitamin K Vitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation, but also a number of other proteins that chelate calcium ion, and are involved in bone and other tissue metabolism. They are 2-methyl-1,4-naphthoquinone derivatives. Cholesterol is an important precursor molecule for the synthesis of Vitamin D and the steroid hormones Steroid hormones are steroids that act as hormones. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens. Vitamin D derivatives are a sixth closely-related hormone system with homologous receptors, though technically sterols rather than, including the adrenal gland hormones cortisol and aldosterone as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.

Some research indicates that cholesterol may act as an antioxidant.^[8]

Dietary sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat contain cholesterol to varying extents.^[9] Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp.^[10]

Human breast milk also contains significant quantities of cholesterol.^[11] Cholesterol is not present in plant-based food sources unless it has been added during the food's preparation.^[10] However, plant products such as flax seeds and peanuts contain cholesterol-like compounds called phytosterols, which are suggested to help lower serum cholesterol levels.^[12]

Total fat intake, especially saturated fat and trans fat,^[13] plays a larger role in blood cholesterol than intake of cholesterol itself. Saturated fat is present in full fat dairy products, animal fats, several types of oil and chocolate. Trans fats are typically derived from the partial hydrogenation of unsaturated fats, and, in contrast to other types of fat, do not occur in significant amounts in nature. Research supports a recommendation to minimize or eliminate trans fats from the diet due to their adverse health effects.^[14] Trans fat is most often encountered in margarine and hydrogenated vegetable fat, and consequently in many fast foods, snack foods, and fried or baked goods.

A change in diet in addition to other lifestyle modifications may help reduce blood cholesterol. Avoiding animal products may decrease the cholesterol levels in the body not only by reducing the quantity of cholesterol consumed but also by reducing the levels of animal-based food consumed and the quantity of cholesterol synthesized. Those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily calories from saturated fat and less than 200 mg of cholesterol per day.^[15]

The view that a change in diet (to be specific, a reduction in dietary fat and cholesterol) can lower blood cholesterol levels, and thus reduce the likelihood of development of, among others, coronary artery disease (CHD) has been challenged. An alternative view is that any reductions to dietary cholesterol intake are counteracted by the organs such as the liver, which will increase or decrease production of cholesterol to keep blood cholesterol levels constant.^[16] Another view is that although saturated fat and dietary cholesterol also raise blood cholesterol, these nutrients are not as effective at doing this as is animal protein.^[17]

Synthesis

About 20–25% of total daily cholesterol production occurs in the liver; other sites of high synthesis rates include the intestines, adrenal glands, and reproductive organs. Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step is the regulated, rate-limiting and irreversible step in cholesterol synthesis and is the site of action for the statin drugs (HMG-CoA reductase competitive inhibitors).

Mevalonate is then converted to 3-isopentenyl pyrophosphate in three reactions that require ATP. This molecule is decarboxylated to isopentenyl pyrophosphate, which is a key metabolite for various biological reactions. Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally, lanosterol is then converted to cholesterol.^[18]

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

Regulation of cholesterol synthesis

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).^[19] In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage-activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site-1 and -2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element), which stimulates the transcription of many genes. Among these are the low-density lipoprotein (LDL) receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.^[20] A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their work. Their subsequent work shows how the SREBP pathway regulates expression of many genes that control lipid formation and metabolism and body fuel allocation.

Cholesterol synthesis can be turned off when cholesterol levels are high, as well. HMG CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain functions to sense signals for its degradation. Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteosome. This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein kinase. Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.^[21]

Plasma transport and regulation of absorption

Cholesterol is only slightly soluble in water; it can dissolve and travel in the water-based bloodstream at exceedingly small concentrations. Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exterior composed of amphiphilic proteins and lipids whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble; triglycerides and cholesterol esters are carried internally. Phospholipids and cholesterol, being amphipathic, are transported in the surface monolayer of the lipoprotein particle.

In addition to providing a soluble means for transporting cholesterol through the blood, lipoproteins have cell-targeting signals that direct the lipids they carry to certain tissues. For this reason, there are several types of lipoproteins within blood called, in order of increasing density, chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The more cholesterol and less protein a lipoprotein has the less dense it is. The cholesterol within all the various lipoproteins is identical, although some cholesterol is carried as the "free" alcohol and some is carried as fatty acyl esters referred to as cholesterol esters. However, the different lipoproteins contain apolipoproteins, which serve as ligands for specific receptors on cell membranes. In this way, the lipoprotein particles are molecular addresses that determine the start- and endpoints for cholesterol transport.

Chylomicrons, the least dense type of cholesterol transport molecules, contain apolipoprotein B-48, apolipoprotein C, and apolipoprotein E in their shells. Chylomicrons are the transporters that carry fats from the intestine to muscle and other tissues that need fatty acids for energy or fat production. Cholesterol, which is not used by muscles, remains in more cholesterol-rich chylomicron remnants, which are taken up from the bloodstream by the liver.

VLDL molecules are produced by the liver and contain excess triacylglycerol and cholesterol that is not required by the liver for synthesis of bile acids. These molecules contain apolipoprotein B100 and apolipoprotein E in their shell. During transport in the bloodstream, the blood vessels cleave and absorb more triacylglycerol to leave IDL molecules, which contain an even higher percentage of cholesterol. The IDL molecules have two possible fates: Half are taken up by the liver for metabolism into other biomolecules and the other half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, which have the highest percentage of cholesterol within them.

LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester. The shell of the LDL molecule contains just one molecule of apolipoprotein B100, which is recognized by the LDL receptor in peripheral tissues. Upon binding of apolipoprotein B100, many LDL receptors become localized in clathrin-coated pits. Both the LDL and its receptor are internalized by endocytosis to form a vesicle within the cell. The vesicle then fuses with a lysosome, which has an enzyme called lysosomal acid lipase that hydrolyzes the cholesterol esters. Now within the cell, the cholesterol can be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with cell membranes.

Synthesis of the LDL receptor is regulated by SREBP, the same regulatory protein as was used to control synthesis of cholesterol de novo in response to cholesterol presence in the cell. When the cell has abundant cholesterol, LDL receptor synthesis is blocked so that new cholesterol in the form of LDL molecules cannot be taken up. On the converse, more LDL receptors are made when the cell is deficient in cholesterol. When this system is deregulated, many LDL molecules appear in the blood without receptors on the peripheral tissues. These LDL molecules are oxidized and taken up by macrophages, which become engorged and form foam cells. These cells often become trapped in the walls of blood vessels and contribute to artherosclerotic plaque formation. These plaques are the main causes of heart attacks, strokes, and other serious medical problems, leading to the association of so-called LDL cholesterol (actually a lipoprotein) with "bad" cholesterol.^[21]

Also, HDL particles are thought to transport cholesterol back to the liver for excretion or to other tissues that use cholesterol to synthesize hormones in a process known as reverse cholesterol transport (RCT).^[22] Having large numbers of large HDL particles correlates with better health outcomes.^[23] In contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Metabolism, recycling and excretion

Cholesterol is oxidized by the liver into a variety of bile acids.^[24] These in turn are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and non-conjugated bile acids along with cholesterol itself is excreted from the liver into the bile. Approximately 95% of the bile acids are reabsorbed from the intestines and the remainder lost in the feces.^[25] The excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation which is essential for the digestion and absorption of dietary fats. Under certain circumstances, when more concentrated, as in the gallbladder, cholesterol crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.^[26]

Clinical significance

Hypercholesterolemia

According to the lipid hypothesis, abnormal cholesterol levels (hypercholesterolemia)—that is, higher concentrations of LDL and lower concentrations of functional HDL—are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke, and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles,^[27] LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices, and other factors.^[28]

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression. A 2007 study pooling data on almost 900,000 subjects in 61 cohorts demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Still, because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is still larger in older people.^[29]

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis).^[30] Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. On the converse, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration.^{[citation needed]} Recently, a post-hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol"^[31]

Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults.^{[citation needed]} As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels,^[32] and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").^[33] Primary prevention in women is practiced only by extension of the findings in studies on men,^[34] since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.^[35]

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.^[36] The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:^[37]

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)^[38], 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—another useful measure—of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL.^{[citation needed]}

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]. The estimated VLDL and LDL have more error when triglycerides are above 200 mg/dL.^[39]

Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some studies have shown an inverse correlation between cholesterol levels and mortality. A 2009 study of patients with acute coronary syndromes found an association of hypercholesterolemia with better mortality outcomes.^[40]. In the Framingham Heart Study, in subjects over 50 years of age they found an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in total cholesterol levels. The researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels.^[41] This explanation is not supported by the Vorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 with very low cholesterol were increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that the low-cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a proxy or marker for frailty occurring with age.^[42]

A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis.^[43] However, the vast majority of doctors and medical scientists accepts the link as fact.^[44]

Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, but some studies suggest a link with depression, cancer, and cerebral hemorrhage. In general, the low cholesterol levels seem to be a consequence of an underlying illness, rather than a cause.^[29]

Cholesterol testing

It is recommended by the American Heart Association to test cholesterol every 5 years for people aged 20 years or older.^[45]

A blood sample after 12-hour fasting is taken by a doctor or a home cholesterol-monitoring device to determine a lipoprotein profile. This measures total cholesterol, LDL (bad) cholesterol, HDL (good) cholesterol, and triglycerides. It is recommended to have cholesterol tested more frequently than 5 years if a person has total cholesterol of 200 mg/dL or more, or if a man over age 45 or a woman over age 50 has HDL (good) cholesterol less than 40 mg/dL, or there exist other risk factors for heart disease and stroke. To convert mg/dl to mmol/L (used in Canada and other parts of the world), divide the mg/dl number by 40.

Cholesteric liquid crystals

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

See also

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

Additional images

References

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External links

• Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults US National Institutes of Health Adult Treatment Panel III
• Aspects of fat digestion and metabolism – UN/WHO Report 1994
• American Heart Association – "About Cholesterol"

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