Jump to content

Cholesterol

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Mindmatrix (talk | contribs) at 15:19, 31 July 2008 (→‎Food sources: drink -> ingest, minor copyedit to simplify sentence). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Template:Chembox new

Microscopic appearance of cholesterol crystals in water. Photo taken under polarized light.

Cholesterol is a lipid found in the cell membranes of all animal tissues, and is transported in the blood plasma of all animals. Cholesterol is also a sterol (a combination steroid and alcohol). Because cholesterol is synthesized by all eukaryotes, trace amounts of cholesterol are also found in membranes of plants and fungi.

The name 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 by François Poulletier de la Salle in 1769. However, it is only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".[1]

Most of the cholesterol in the body 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 and brain. It plays a central role in many biochemical processes, such as the composition of cell membranes and the synthesis of steroid hormones.[2]

Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exterior composed mainly of water-soluble proteins; fats and cholesterol are carried internally. There is a large range of lipoproteins within blood, generally called, from larger to smaller size: chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). The cholesterol within all the various lipoproteins is identical.

According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia), or, more correctly, 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 [3], 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 colloquially as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices and other factors.[4]

Physiology

Function

Cholesterol is required to build and maintain cell membranes; it regulates membrane fluidity over a wide range of temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospho- and sphingolipids, while the bulky steroid and the hydrocarbon chain is embedded in the membrane, alongside the nonpolar fatty acid chains of the other lipids. Some research indicates that cholesterol may act as an antioxidant.[5] 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 A, D, E and K. It is the major precursor for the synthesis of vitamin D and 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).

Recently, cholesterol has also been implicated in cell signaling processes, where it has been suggested that it assists in the formation of lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to hydrogen ions (protons) and sodium ions.[6]

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.

Synthesis and intake

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 LDL 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% of 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), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200–300 mg in the United States and societies adopting its dietary patterns. Of the cholesterol input to the intestines via bile production, 92–97% 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. 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). 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) 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.[7]

A large part of this mechanism 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.

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.

In blood

See also: Blood lipids

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.

Cholesterol is transported towards peripheral tissues by the lipoproteins chylomicrons, very low density lipoproteins (VLDL) and low-density lipoproteins (LDL). 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".

On the other hand, high-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion. 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.

Clinical significance

Hypercholesterolemia

Main articles: hypercholesterolemia and lipid hypothesis

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.[8] There remains some opposition to the link between cholesterol and coronary heart disease, termed the "lipid hypothesis".[citation needed]

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis).[citation needed] 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.[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".[9]

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. As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels,[10] and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").[11] Primary prevention in women is practiced only by extension of the findings in studies on men,[12] since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.[13]

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.[14]. The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:[15]

Level mg/dL Level mmol/L Interpretation
< 200 < 5.2 Desirable level corresponding to lower risk for heart disease
200–240 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)[15], 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.

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] − [total HDL] − 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 eight hours before the blood test because the triglyceride level varies significantly with food intake.

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 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. In the Framingham Heart Study, the researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels.[16] 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.[17]

A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis.[18] However, the vast majority of doctors and medical scientists accepts the link as fact.[19]

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. Generally, the low cholesterol levels seem to be a consequence of an underlying illness, rather than a cause.[8]

Cholesterol testing

It is recommended by the American Heart Association to test cholesterol every 5 years for people aged 20 years or older. [20] A blood sample taken after 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, is a man over age 45 or a woman over age 50, has HDL (good) cholesterol less than 40 mg/dL, or other risk factors for heart disease and stroke.

Food sources

Cholesterol is mostly found in animal fats: all food containing animal fats contains cholesterol;[citation needed]; however food not containing animal fats also contains cholesterol in varying amounts. Major dietary sources of cholesterol include egg yolks, beef, poultry, and shrimp.[21] Human breast milk also contains significant quantities of cholesterol.[22]

Plants have trace amounts of cholesterol, so even a vegan diet, which includes no animal foods, can have a high amount of cholesterol depending on the diet and oils used. For example, to ingest the amount of cholesterol in one egg yolk, one would need to ingest about 9.6 litres (2.1 imp gal; 2.5 US gal) of pure peanut oil.[15][failed verification] [23][failed verification] However unlike peanut oil, which is considered to contain "good" cholesterol, other oils like coconut oil and palm oil contain at least as much cholesterol as animal fats.[24]

Plant products (e.g. flax seeds, peanuts), also contain cholesterol-like compounds, phytosterols, which are suggested to help lower serum cholesterol.[25]

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

Additional images

Footnotes

  1. ^ Olson RE (1998). "Discovery of the lipoproteins, their role in fat transport and their significance as risk factors". J. Nutr. 128 (2 Suppl): 439S–443S. PMID 9478044.
  2. ^ Stryer, Lubert (1995). Biochemistry (4th ed. ed.). New York: W.H. Freeman & co. pp. 280, 703. ISBN 0-7167-2009-4. {{cite book}}: |edition= has extra text (help)
  3. ^ Brunzell JD; et al. (2008). "Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation – Lipoprotein management in patients with cardiometabolic risk". Diabetes Care. 31 (4): 811–822. doi:10.2337/dc08-9018. PMID 18375431. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
  4. ^ Durrington P (2003). "Dyslipidaemia". Lancet. 362 (9385): 717–31. doi:10.1016/S0140-6736(03)14234-1. PMID 12957096.
  5. ^ Smith LL (1991). "Another cholesterol hypothesis: cholesterol as antioxidant". Free Radic. Biol. Med. 11 (1): 47–61. PMID 1937129.
  6. ^ Haines TH (2001). "Do sterols reduce proton and sodium leaks through lipid bilayers?". Prog. Lipid Res. 40 (4): 299–324. PMID 11412894.
  7. ^ Brown MS, Goldstein JL (1997). "The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor". Cell. 89: 331. doi:10.1016/S0092-8674(00)80213-5. PMID 9150132.
  8. ^ a b Lewington S, Whitlock G, Clarke R; et al. (2007). "Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths". Lancet. 370 (9602): 1829–39. doi:10.1016/S0140-6736(07)61778-4. PMID 18061058. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ van der Steeg WA (2008). "High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies". J Am Coll Cardiol. 51 (6): 634–642. doi:10.1016/j.jacc.2007.09.060. PMID 18261682.
  10. ^ "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial". Lancet. 360 (9326): 7–22. 2002. PMID 12114036.
  11. ^ Shepherd J, Cobbe SM, Ford I; et al. (1995). "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group". N. Engl. J. Med. 333 (20): 1301–7. PMID 7566020. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  12. ^ Grundy SM (2007). "Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? Yes". BMJ. 334 (7601): 982. doi:10.1136/bmj.39202.399942.AD. PMID 17494017.
  13. ^ Kendrick M (2007). "Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? No". BMJ. 334 (7601): 983. doi:10.1136/bmj.39202.397488.AD. PMID 17494018.
  14. ^ "Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel". Arch. Intern. Med. 148 (1): 36–69. 1988. PMID 3422148.
  15. ^ a b c "About cholesterol" – American Heart Association
  16. ^ Anderson KM., Castelli WP, Levy D. (1987). "Cholesterol and mortality. 30 years of follow-up from the Framingham study". JAMA. 257: 2176–80. doi:10.1001/jama.257.16.2176. PMID 3560398.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Ulmer H., Kelleher C., Diem G., Concin H. (2004). "Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality". J Women's Health (Larchmt). 13: 41–53. doi:10.1089/154099904322836447. PMID 15006277.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Uffe Ravnskov. The Cholesterol Myths : Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease. New Trends Publishing, Incorporated. ISBN 0-96708-970-0.
  19. ^ Daniel Steinberg. The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. Boston: Academic Press. ISBN 0-12-373979-9.
  20. ^ American Heart Association. "How To Get Your Cholesterol Tested".
  21. ^ Nutrition and Your Health: Dietary Guidelines for Americans. Table E-18. Dietary Sources of Cholesterol Listed in Decreasing Order.
  22. ^ Jensen RG, Hagerty MM, McMahon KE (1978). "Lipids of human milk and infant formulas: a review" (PDF). Am J Clin Nutr. 31: 990–1016. PMID 352132.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Behrman EJ, Gopalan V. Cholesterol and plants. J Chem Educ 2005;82:1791–1793. PDF
  24. ^ [Is It True That Coconut Oil May Help Lower Cholesterol?] By Dr. James J. (Jay) Kenney, PhD, RD, FACN
  25. ^ Ostlund RE, Racette, SB, and Stenson WF (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Template:Link FA

Retrieved from "https://en.wikipedia.org/w/index.php?title=Cholesterol&oldid=229030408"