|Molecular mass||386.65 g/mol|
|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)|
|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).
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).
Synthesis and intake
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 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.
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).
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.
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.
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.
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|
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.
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).
- 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.
All links retrieved February 16, 2017.
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