Cholesterol

Cholesterol is a lipid like, waxy alcohol found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity. Cholesterol is the principal sterol synthesized by animals while smaller quantities are synthesized in other eukaryotes such as plants and fungi. In contrast, cholesterol is almost completely absent among prokaryotes such as bacteria. Cholesterol is classified as a sterol (a contraction of steroid and alcohol).

While minimum levels of cholesterol are essential for life, excess levels in the circulation are associated with atherosclerosis. Cholesterol is synthesized by virtually all the body cells but significant quantities can also be absorbed from the diet.

Physiology

Function

Cholesterol is required to build and maintain cell membranes; it regulates membrane fluidity over a wide range of temperatures. The liver produces about 1 gram of cholesterol per day through the bile, which contains cholesterol. 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.[4] 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). It is the base structure for steroids. It also covers nerves in the form of myelin. This helps to conduct nerve impulses.

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.

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 absorption

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.

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.

Plasma transport

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 lipoproteinsis identical.

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 in a process known as reverse cholesterol transport (RCT). Having large numbers of large HDL particles correlates with better health outcomes. In contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Homeostasis

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.

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 Physiolo gy 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.

Metabolism and excretion

Cholesterol is oxidized by the liver into variety of bile acids. These in turnare 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. 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.

Dietary sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. Consequently all foods containing animal fat contain cholesterol to varying extents. Cholesterol is not present in plant based food sources unless it has been added during the foods preparation. However plant products such as flax seeds and peanuts contain healthy cholesterol-like compounds called phytosterols, which are suggested to help lower serum cholesterol levels. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp. Human breast milk also contains significant quantities of cholesterol.

Dietary cholesterol plays a smaller role in blood cholesterol levels in comparison to fat intake. A number of measures can be taken to reduce blood cholesterol levels through changes in lifestyle, one of which is a change in diet. Trans and saturated fats are a significant contributors to elevated cholesterol levels in the blood stream. Avoiding animal products may decrease the cholesterol levels in the body not through dietary cholesterol reduction alone, but primarily through a reduced saturated fat intake. 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 200mg of cholesterol per day.

Clinical significance

Hypercholesterolemia

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, 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.

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.

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. 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".

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, and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention"). Primary prevention in women is practiced only by extension of the findings in studies on men, since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: <> 240 mg/dL high cholesterol. The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:

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)[27], although a newer target of <> 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. 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.

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

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.

Cholesterol testing

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

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.