Hypercholesterolemia

From Wikipedia, the free encyclopedia

Hypercholesterolemia
Synonyms	Hypercholesterolaemia, high cholesterol
Xanthelasma palpebrarum, yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with familial hypercholesterolemia.
Specialty	Cardiology

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia (elevated levels of lipoproteins in the blood).

Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as type 2 diabetes and an underactive thyroid.

Cholesterol is one of three major classes of lipids which all animal cells use to construct their membranes and is thus manufactured by all animal cells. Plant cells do not manufacture cholesterol. It is also the precursor of the steroid hormones and bile acids. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease. In contrast, higher levels of HDL cholesterol are protective.

Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults. In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required. If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed. About 34 million adults in the United States have high blood cholesterol.

Signs and symptoms

Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (hardening of arteries). Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow. A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.

Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers. Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.

Causes

Formula structure of cholesterol

Hypercholesterolemia is typically due to a combination of environmental and genetic factors. Environmental factors include weight, diet, and stress.

A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis, nephrotic syndrome, hypothyroidism, Cushing’s syndrome, anorexia nervosa, medications (e.g., thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics).

Genetic contributions are usually due to the additive effects of multiple genes, though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia. and Acute Intermittent Porphyria, a mutation of the HMBS gene. 

Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia, where one or more genetic mutations in the autosomal dominant APOB gene exist, the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. Familial hypercholesterolemia affects about one in five hundred people.

Diet

Diet has an effect on blood cholesterol, but the size of this effect varies between individuals. Moreover, when dietary cholesterol intake goes down, production (principally by the liver) typically increases, so that blood cholesterol changes can be modest or even elevated. This compensatory response may explain hypercholesterolemia in anorexia nervosa. A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol. Trans fats have been shown to reduce levels of HDL while increasing levels of LDL. LDL and total cholesterol also increases by very high fructose intake.

Hormonal effects

Glucocorticoids increase cholesterol LDL production by increasing production and activity of HMG-CoA reductase. These include the physiologic stress hormone cortisol and commonly used medicines for asthma, rheumatoid arthritis, or connective tissue disorders. Other steroid hormones and drugs are also implicated. In contrast, the thyroid hormone decreases cholesterol production. Hence, hypothyroidism (lack of thyroid hormone) causes hypercholesterolemia.

Medications

Hypercholesterolemia may be a side effect of a number of medications, including blood pressure medication, antipsychotics, anticonvulsants, immunosuppressives, human immunodeficiency virus therapy, and interferons.

Diagnosis

Interpretation of cholesterol levels
cholesterol type	mg/dL	mmol/L	interpretation
total cholesterol	<200 span="">	<5 .2="" span="">	desirable
	200–239	5.2–6.2	borderline
	>240	>6.2	high
LDL cholesterol	<100 span="">	<2 .6="" span="">	most desirable
	100–129	2.6–3.3	good
	130–159	3.4–4.1	borderline high
	160–189	4.1–4.9	high and undesirable
	>190	>4.9	very high
HDL cholesterol	<40 span="">	<1 .0="" span="">	undesirable; risk increased
	41–59	1.0–1.5	okay, but not optimal
	>60	>1.55	good; risk lowered

Indications to lower LDL cholesterol
Coronary risk	because they have...	should consider	reduction indicated
high	>20% risk of MI in 10 years, or risk factor such as coronary heart disease, diabetes, peripheral-artery disease, carotid-artery disease, or aortic aneurysm	>70 mg/dL, 3.88 mmol/L especially if there are risk factors	>100 mg/dL, 5.55 mmol/L
moderately high	10–20% risk of MI in 10 years and > 1 risk factors	>100 mg/dL, 5.55 mmol/L	>130 mg/dL, 7.21 mmol/L
moderate	<10 10="" in="" mi="" of="" risk="" years=""> 1 risk factors	>130 mg/dL, 7.21 mmol/L	>160 mg/dL, 8.88 mmol/L
low	No or one risk factor	>160 mg/dL, 8.88 mmol/L	>190 mg/dL, 10.5 mmol/L

Cholesterol is measured in milligrams per deciliter (mg/dL) of blood in the United States and some other countries. In the United Kingdom, most European countries and Canada, millimoles per liter of blood (mmol/Ll) is the measure.

For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol is 4 mmol/L, and 2 mmol/L for LDL.

In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as “desirable,” 200 to 239 mg/dL as “borderline high,” and 240 mg/dL or more as “high”.

No absolute cutoff between normal and abnormal cholesterol levels exists, and interpretation of values must be made in relation to other health conditions and risk factors.

Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease. Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed. High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction. In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides is composed of VLDL), while LDL was usually estimated by the Friedewald formula:

LDL ${\displaystyle \approx }$ total cholesterol - HDL - (0.2 x fasting triglycerides).

However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated more than 4.5 mmol/L (more than ∼400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for measurement of LDL wherever possible. It may be useful to measure all lipoprotein subfractions ( VLDL, IDL, LDL, and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value. Genetic screening is now advised if a form of familial hypercholesterolemia is suspected.

Classification

Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as "lipoprotein subclass analysis", have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences. If the hypercholesterolemia is hereditary (familial hypercholesterolemia), more often a family history of premature, earlier onset atherosclerosis is found.

Screening

Two bags of fresh frozen plasma: The bag on the left was obtained from a donor with hyperlipidemia, while the other bag was obtained from a donor with normal serum lipid levels.

 

The U.S. Preventive Services Task Force in 2008 strongly recommends routine screening for men 35 years and older and women 45 years and older for lipid disorders and the treatment of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for coronary heart disease. In 2016 they concluded that testing the general population under the age of 40 without symptoms is of unclear benefit.

In Canada, screening is recommended for men 40 and older and women 50 and older. In those with normal cholesterol levels, screening is recommended once every five years. Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.

Treatment

For those at high risk, a combination of lifestyle modification and statins has been shown to decrease mortality.

Lifestyle

Lifestyle changes recommended for those with high cholesterol include: smoking cessation, limiting alcohol consumption, increasing physical activity, and maintaining a healthy weight.

Overweight or obese individuals can lower blood cholesterol by losing weight – on average a kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dl.

Diet

Eating a diet with a high proportion of vegetables, fruit, dietary fiber, and low in fats results in a modest decrease in total cholesterol.

Eating dietary cholesterol causes a small but significant rise in serum cholesterol. Dietary limits for cholesterol were proposed in United States, but not in Canada, United Kingdom, and Australia. Consequently, in 2015 the Dietary Guidelines Advisory Committee in the United States removed its recommendation of limiting cholesterol intake.

A 2015 Cochrane review found replacing saturated fat with polyunsaturated fat resulted in a small decrease in cardiovascular disease by decreasing blood cholesterol. Other reviews have not found an effect from saturated fats on cardiovascular disease. Trans fats are recognized as a potential risk factor for cholesterol-related cardiovascular disease, and avoiding them in an adult diet is recommended.

The National Lipid Association recommends that people with familial hypercholesterolemia restrict intakes of total fat to 25–35% of energy intake, saturated fat to less than 7% of energy intake, and cholesterol to less than 200 mg per day. Changes in total fat intake in low calorie diets do not appear to affect blood cholesterol.

Increasing soluble fiber consumption has been shown to reduce levels of LDL cholesterol, with each additional gram of soluble fiber reducing LDL by an average of 2.2 mg/dL (0.057 mmol/L). Increasing consumption of whole grains also reduces LDL cholesterol, with whole grain oats being particularly effective. Inclusion of 2 g per day of phytosterols and phytostanols and 10 to 20 g per day of soluble fiber decreases dietary cholesterol absorption. A diet high in fructose can raise LDL cholesterol levels in the blood.

Medication

Statins are the typically used medications, in addition to healthy lifestyle interventions. Statins can reduce total cholesterol by about 50% in the majority of people, and are effective in reducing the risk of cardiovascular disease in both people with and without pre-existing cardiovascular disease. In people without cardiovascular disease, statins have been shown to reduce all-cause mortality, fatal and non-fatal coronary heat disease, and strokes. Greater benefit is observed with the use of high-intensity statin therapy. Statins may improve quality of life when used in people without existing cardiovascular disease (i.e. for primary prevention). Statins decrease cholesterol in children with hypercholesterolemia, but no studies as of 2010 show improved outcomes and diet is the mainstay of therapy in childhood.

Other agents that may be used include fibrates, nicotinic acid, and cholestyramine. These, however, are only recommended if statins are not tolerated or in pregnant women. Injectable antibodies against the protein PCSK9 (evolocumab, bococizumab, alirocumab) can reduce LDL cholesterol and have been shown to reduce mortality.

Alternative medicine

According to a survey in 2002, alternative medicine was used in an attempt to treat cholesterol by 1.1% of U.S. adults. Consistent with previous surveys, this one found the majority of individuals (55%) used it in conjunction with conventional medicine. A review of trials of phytosterols and/or phytostanols, average dose 2.15 g/day, reported an average of 9% lowering of LDL-cholesterol. In 2000, the Food and Drug Administration approved the labeling of foods containing specified amounts of phytosterol esters or phytostanol esters as cholesterol-lowering; in 2003, an FDA Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering more than 0.8 g/day of phytosterols or phytostanols. Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to lack of long-term safety data.

Epidemiology

Rates of high total cholesterol in the United States in 2010 are just over 13%, down from 17% in 2000.

Average total cholesterol in the United Kingdom is 5.9 mmol/L, while in rural China and Japan, average total cholesterol is 4 mmol/L. Rates of coronary artery disease are high in Great Britain, but low in rural China and Japan.

Research

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia.

The National Cholesterol Education Program revised their guidelines; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.

In the UK, the National Institute for Health and Clinical Excellence has made recommendations for the treatment of elevated cholesterol levels, published in 2008.

The Task Force for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society published guidelines for the management of dyslipidaemias in 2011.

Gene therapy is being studied as a potential treatment.

Special populations

Among people whose life expectancy is relatively short, hypercholesterolemia is not a risk factor for death by any cause including coronary heart disease. Among people older than 70, hypercholesterolemia is not a risk factor for being hospitalized with myocardial infarction or angina. There are also increased risks in people older than 85 in the use of statin drugs. Because of this, medications which lower lipid levels should not be routinely used among people with limited life expectancy.

The American College of Physicians recommends for hypercholesterolemia in people with diabetes:

• Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all adults with known coronary artery disease and type 2 diabetes.
• Statins should be used for primary prevention against macrovascular complications in adults with type 2 diabetes and other cardiovascular risk factors.
• Once lipid-lowering therapy is initiated, people with type 2 diabetes mellitus should be taking at least moderate doses of a statin.
• For those people with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

Cholesterol (updated)

From Wikipedia, the free encyclopedia

Cholesterol

Names
IUPAC name (3β)-cholest-5-en-3-ol
Systematic IUPAC name (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol
Other names Cholesterin, Cholesteryl alcohol
Identifiers
CAS Number	57-88-5
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16113
ChEMBL	ChEMBL112570
ChemSpider	5775
ECHA InfoCard	100.000.321
IUPHAR/BPS	2718
KEGG	D00040
PubChem CID	5997
UNII	97C5T2UQ7J
Properties
Chemical formula	C27H46O
Molar mass	386.65 g/mol
Appearance	white crystalline powder
Density	1.052 g/cm3
Melting point	148 to 150 °C (298 to 302 °F; 421 to 423 K)
Boiling point	360 °C (680 °F; 633 K) (decomposes)
Solubility in water	1.8 mg/L (30 °C) 0.095 mg/L (30 °C)
Solubility	soluble in acetone, benzene, chloroform, ethanol, ether, hexane, isopropyl myristate, methanol
Magnetic susceptibility (χ)	-284.2·10−6 cm3/mol
Hazards
Flash point	209.3 ±12.4 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Cholesterol (from the Ancient Greek chole- (bile) and stereos (solid), followed by the chemical suffix -ol for an alcohol) is an organic molecule. It is a sterol (or modified steroid), a type of lipid molecule, and is biosynthesized by all animal cells, because it is an essential structural component of all animal cell membranes.

In addition to its importance for animal cell structure, cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acid and vitamin D. Cholesterol is the principal sterol synthesized by all animals. In vertebrates, hepatic cells typically produce the greatest amounts. It is absent among prokaryotes (bacteria and archaea), although there are some exceptions, such as Mycoplasma, which require cholesterol for growth.

François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until 1815 that chemist Michel Eugène Chevreul named the compound "cholesterine".

Physiology

Since cholesterol is essential for all animal life, each cell is capable of synthesizing it by way of a complex 37-step process, beginning with the mevalonate pathway and ending with a 19-step conversion of lanosterol to cholesterol. Furthermore, it can be absorbed directly from animal-based foods. 

A human male weighing 68 kg (150 lb) normally synthesizes about 1 gram (1,000 mg) per day, and his body contains about 35 g, mostly contained within the cell membranes. Typical daily cholesterol dietary intake for a man in the United States is 307 mg.

Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. The body also compensates for any absorption of additional cholesterol by reducing cholesterol synthesis. For these reasons, cholesterol in food, seven to ten hours after ingestion, has little, if any effect on concentrations of cholesterol in the blood. However, during the first seven hours after ingestion of cholesterol, as absorbed fats are being distributed around the body within extracellular water by the various lipoproteins (which transport all fats in the water outside cells), the concentrations increase. It is also important to recognize, however, that the concentrations measured in the samples of blood plasma vary with the measurement methods used. Traditional, cheaper methods do not reflect (a) which lipoproteins are transporting the various fat molecules, nor (b) which cells are ingesting, burning or exporting the fat molecules being measured as totals from samples of blood plasma.

Cholesterol is recycled in the body. The liver excretes it in a non-esterified form (via bile) into the digestive tract. Typically, about 50% of the excreted cholesterol is reabsorbed by the small intestine back into the bloodstream

.

Plants make cholesterol in very small amounts. Plants manufacture phytosterols (substances chemically similar to cholesterol), which can compete with cholesterol for reabsorption in the intestinal tract, thus potentially reducing cholesterol reabsorption. When intestinal lining cells absorb phytosterols, in place of cholesterol, they usually excrete the phytosterol molecules back into the GI tract, an important protective mechanism. The intake of naturally occurring phytosterols, which encompass plant sterols and stanols, ranges between ~200–300 mg/day depending on eating habits. Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day.

Function

Cholesterol, given that it composes about 30% of all animal cell membranes, is required to build and maintain membranes and modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group of each cholesterol molecule interacts with the water molecules surrounding the membrane as do the polar heads of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which both alters membrane fluidity and maintains membrane integrity so that animal cells do not need to build cell walls (like plants and most bacteria). The membrane remains stable and durable without being rigid, allowing animal cells to change shape and animals to move. 

The structure of the tetracyclic ring of cholesterol contributes to the fluidity of the cell membrane, as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar. In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes, hydrogen ions, and sodium ions.

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. The role of cholesterol in endocytosis of these types can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. Recent studies show that cholesterol is also implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane, which brings receptor proteins in close proximity with high concentrations of second messenger molecules. In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses. Demyelination (loss of some of these Schwann cells) is believed to be part of the basis for multiple sclerosis.

Within cells, cholesterol is also a precursor molecule for several biochemical pathways. For example, it is the precursor molecule for the synthesis of vitamin D and all steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.

The liver excretes cholesterol into biliary fluids, which is then stored in the gallbladder. 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, A, D, E, and K.

Biosynthesis and regulation

Biosynthesis

All animal cells manufacture cholesterol, for both membrane structure and other uses, with relative production rates varying by cell type and organ function. About 80% of total daily cholesterol production occurs in the liver and the intestines; other sites of higher synthesis rates include adrenal glands, and reproductive organs. 

Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl CoA condense to form acetoacetyl-CoA. This is followed by a second condensation between acetyl CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).

This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. Production of mevalonate is the rate-limiting and irreversible step in cholesterol synthesis and is the site of action for statins (a class of cholesterol lowering drugs). 

Mevalonate is finally converted to isopentenyl pyrophosphate (IPP) through two phosphorylation steps and one decarboxylation step that requires ATP. 

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 converted to cholesterol through a 19-step process.

The final 19 steps to cholesterol contain NADPH and oxygen to help oxidize methyl groups for removal of carbons, mutases to move alkene groups, and NADH to help reduce ketones. 

Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning some of the mechanisms and methods of 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). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP cleavage-activating protein) and INSIG-1. When cholesterol levels fall, INSIG-1 dissociates from the SREBP-SCAP complex, which allows the complex to migrate to the Golgi apparatus. Here SREBP is cleaved by S1P and S2P (site-1 protease and site-2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. 

The cleaved SREBP then migrates to the nucleus, and acts as a transcription factor to bind to the sterol regulatory element (SRE), which stimulates the transcription of many genes. Among these are the low-density lipoprotein (LDL) receptor and HMG-CoA reductase. The LDL receptor 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 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 also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain senses 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.

Plasma transport and regulation of absorption

Lipid logistics: transport of triglycerides and cholesterol in organisms in form of lipoproteins as chylomicrons, VLDL, LDL, IDL, HDL.

 

As an isolated molecule, cholesterol is only minimally soluble in water; it dissolves into the (water-based) bloodstream only at exceedingly small concentrations. Instead, cholesterol is transported within lipoproteins, complex discoidal particles with exterior amphiphilic proteins and lipids, whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble; i.e. transport via emulsification. Triglycerides and cholesterol esters are carried internally. Phospholipids and cholesterol, being amphipathic, are transported in the monolayer surface of the lipoprotein particle.

There are several types of lipoproteins in the blood. In order of increasing density, they are chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Lower protein/lipid ratios make for less dense lipoproteins. Cholesterol within different lipoproteins is identical, although some is carried as its native "free" alcohol form (the cholesterol-OH group facing the water surrounding the particles), while others as fatty acyl esters, known also as cholesterol esters, within the particles.

Lipoprotein particles are organized by complex apolipoproteins, typically 80–100 different proteins per particle, which can be recognized and bound by specific receptors on cell membranes, directing their lipid payload into specific cells and tissues currently ingesting these fat transport particles. Lipoprotein particles thus include a molecular addresses which play key roles in distribution and delivery of fats around the body in the water outside cells.

Chylomicrons, the least dense cholesterol transport molecules, contain apolipoprotein B-48, apolipoprotein C, and apolipoprotein E (the principal cholesterol carrier in the brain) in their shells. Chylomicrons carry fats from the intestine to muscle and other tissues in need of fatty acids for energy or fat production. Unused cholesterol remains in more cholesterol-rich chylomicron remnants, and taken up from here to the bloodstream by the liver. 

VLDL molecules are produced by the liver from triacylglycerol and cholesterol which was not used in the synthesis of bile acids. These molecules contain apolipoprotein B100 and apolipoprotein E in their shells, and are degraded by lipoprotein lipase on the blood vessel wall to IDL.

Blood vessels cleave and absorb triacylglycerol from IDL molecules, increasing the concentration of cholesterol. IDL molecules are then consumed in two processes: half is metabolized by HTGL and taken up by the LDL receptor on the liver cell surfaces, while the other half continues to lose triacylglycerols in the bloodstream until they become LDL molecules, with the highest concentration of cholesterol within them.

LDL particles are the major blood cholesterol carriers. Each one contains approximately 1,500 molecules of cholesterol ester. LDL molecule shells contain just one molecule of apolipoprotein B100, recognized by LDL receptors in peripheral tissues. Upon binding of apolipoprotein B100, many LDL receptors concentrate in clathrin-coated pits. Both LDL and its receptor form vesicles within a cell via endocytosis. These vesicles then fuse with a lysosome, where the lysosomal acid lipase enzyme hydrolyzes the cholesterol esters. The cholesterol can then be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with the cell membranes.

LDL receptors are used up during cholesterol absorption, and its synthesis is regulated by SREBP, the same protein that controls the synthesis of cholesterol de novo, according to its presence inside the cell. A cell with abundant cholesterol will have its LDL receptor synthesis blocked, to prevent new cholesterol in LDL molecules from being taken up. Conversely, LDL receptor synthesis proceeds when a cell is deficient in cholesterol.

When this process becomes unregulated, LDL molecules without receptors begin to appear in the blood. These LDL molecules are oxidized and taken up by macrophages, which become engorged and form foam cells. These foam cells often become trapped in the walls of blood vessels and contribute to atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness). 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.

HDL particles are thought to transport cholesterol back to the liver, either for excretion or for other tissues that synthesize hormones, in a process known as reverse cholesterol transport (RCT). Large numbers of HDL particles correlates with better health outcomes, whereas low numbers of HDL particles is associated with atheromatous disease progression in the arteries.

Metabolism, recycling and excretion

Cholesterol is susceptible to oxidation and easily forms oxygenated derivatives called oxysterols. Three different mechanisms can form these: autoxidation, secondary oxidation to lipid peroxidation, and cholesterol-metabolizing enzyme oxidation. A great interest in oxysterols arose when they were shown to exert inhibitory actions on cholesterol biosynthesis. This finding became known as the “oxysterol hypothesis”. Additional roles for oxysterols in human physiology include their participation in bile acid biosynthesis, function as transport forms of cholesterol, and regulation of gene transcription.

In biochemical experiments radiolabelled forms of cholesterol, such as tritiated-cholesterol are used. These derivatives undergo degradation upon storage and it is essential to purify cholesterol prior to use. Cholesterol can be purified using small Sephadex LH-20 columns.

Cholesterol is oxidized by the liver into a variety of bile acids. These, in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and nonconjugated 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 are 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 (lecithin and bilirubin gallstones also occur, but less frequently). Every day, up to 1 g of cholesterol enters the colon. This cholesterol originates from the diet, bile, and desquamated intestinal cells, and can be metabolized by the colonic bacteria. Cholesterol is converted mainly into coprostanol, a nonabsorbable sterol that is excreted in the feces. A cholesterol-reducing bacterium origin has been isolated from human feces.

Although cholesterol is a steroid generally associated with mammals, the human pathogen Mycobacterium tuberculosis is able to completely degrade this molecule and contains a large number of genes that are regulated by its presence. Many of these cholesterol-regulated genes are homologues of fatty acid β-oxidation genes, but have evolved in such a way as to bind large steroid substrates like cholesterol.

Dietary sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of both the phospholipids and cholesterol molecules from which all animal (and human) cell membranes are constructed. Since all animal cells manufacture cholesterol, all animal-based foods contain cholesterol in varying amounts. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, fish, and shrimp. Human breast milk also contains significant quantities of cholesterol.

Plant cells synthesize cholesterol as a precursor for other compounds, such as phytosterols and steroidal glycoalkaloids, with cholesterol remaining in plant foods only in minor amounts or absent. Some plant foods, such as avocado, flax seeds and peanuts, contain phytosterols, which compete with cholesterol for absorption in the intestines, reduce the absorption of both dietary and bile cholesterol. A typical diet contributes on the order of 0.2 gram of phytosterols, which is not enough to have a significant impact on blocking cholesterol absorption. Phytosterols intake can be supplemented through the use of phytosterol-containing functional foods or dietary supplements that are recognized as having potential to reduce levels of LDL-cholesterol. Some supplemental guidelines have recommended doses of phytosterols in the 1.6–3.0 grams per day range (Health Canada, EFSA, ATP III, FDA). A recent meta-analysis demonstrating a 12% reduction in LDL-cholesterol at a mean dose of 2.1 grams per day. However, the benefits of a diet supplemented with phytosterols have been questioned.

In 2016, the United States Department of Agriculture Dietary Guidelines Advisory Committee recommended that Americans eat as little dietary cholesterol as possible. Increased dietary intake of industrial trans fats is associated with an increased risk in all-cause mortality and cardiovascular diseases. Trans fats have been shown to correlate with reduced levels of HDL and increased levels of LDL. Based on this evidence, along with other claims implicating low HDL and high LDL levels in cardiovascular disease, many health authorities advocate reducing LDL-cholesterol through changes in diet in addition to other lifestyle modifications. The related studies which correlate trans fats, as well as saturated fats, with unhealthy serum cholesterol levels, have since been contested on numerous points. The most notable and egregious challenge to these standards comes from a NCBI published meta analysis of the data used in the development of these guidelines, in which the correlation between serum cholesterol and saturated fat intake, was similarly or less significant than the correlation to visceral fat. As well as others, one of which concluded that current evidence "does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats." Other evidences such as metabolic ward and lab studies, including a study where rats subjected to high-fat or fructose diets became dyslipidemic are similarly questionable, given indications of an increase of produced visceral fat, which occurs as a result of metabolic differences in the processing of fructose. A general inconsistency of conclusions regarding the impact of simple carbohydrates on visceral fat, and a lack of data regarding the causal relationship between serum cholesterol and either saturated fat and visceral fat, makes drawing a definitive conclusion unreasonable, especially given the presence of numerous correlations. As such, given that well designed, adequately powered randomized controlled trials investigating patient-relevant outcomes of low-fat diets for otherwise healthy people with hypercholesterolaemia are lacking; large, parallel, randomized controlled trials are still needed to investigate the effectiveness of a cholesterol-lowering diet and the addition of omega-3 fatty acids, soya protein, plant sterols or stanols, especially in the case of familial hypercholesterolemia.

Research

Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor, GABA_A receptor, and the inward-rectifier potassium ion channel. Cholesterol also activates the estrogen-related receptor alpha (ERRα), and may be the endogenous ligand for the receptor. The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body. Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of the effects of statins and bisphosphonates on bone, muscle, and macrophages. On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol.

Clinical significance

Hypercholesterolemia

Cholesterolemia and mortality for men and women more than 50 years and 60 years of age

 

According to the lipid hypothesis, since cholesterol (like all fat molecules) is transported around the body (in the water outside cells) inside lipoprotein particles, elevated cholesterol concentrations (hypercholesterolemia) potentially offer a lower cost way to estimate concentrations of LDL particles; possibly even low concentrations of functional HDL particles, both variations strongly associated with cardiovascular disease because LDL particles promote atheroma development in arteries (atherosclerosis).

This atherosclerotic disease process, over decades, 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 HDL 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 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. 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".

Elevated cholesterol levels are treated with a strict diet consisting of low saturated fat, trans fat-free, low cholesterol foods, often followed by one of various hypolipidemic agents, such as statins, fibrates, cholesterol absorption inhibitors, nicotinic acid derivatives or bile acid sequestrants. Extreme cases have previously been treated with partial ileal bypass surgery, which has now been superseded by medication. Apheresis-based treatments are still used for very severe hyperlipidemias that are either unresponsive to treatment or require rapid lowering of blood lipids. There are several international guidelines on the treatment of hypercholesterolaemia.

Multiple human trials using 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. Studies have also found that statins reduce atheroma progression. As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels (total cholesterol below 5.0 mmol/L [193 mg/dL]), and in men without cardiovascular disease, there is benefit from lowering abnormally high cholesterol levels ("primary prevention"). Primary prevention in women was originally practiced only by extension of the findings in studies on men, since, in women, none of the large statin trials conducted prior to 2007 demonstrated a statistically significant reduction in overall mortality or in cardiovascular endpoints. In 2008, a large clinical trial reported that, in apparently healthy adults with increased levels of the inflammatory biomarker high-sensitivity C-reactive protein but with low initial LDL, 20 mg/day of rosuvastatin for 1.9 years resulted in a 44% reduction in the incidence of cardiovascular events and a 20% reduction in all-cause mortality; the effect was statistically significant for both genders. Though this result was met with some skepticism, later studies and meta-analyses likewise demonstrated statistically significant (but smaller) reductions in all-cause and cardiovascular mortality, without significant heterogeneity by gender.

Level mg/dL	Level mmol/L	Interpretation
less than 200	less than 5.2	Desirable level corresponding to lower risk for heart disease
200–240	5.2–6.2	Borderline high risk
more than 240	more than 6.2	High risk

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggests the total blood cholesterol level should be: less than 200 mg/dL normal blood cholesterol, 200–239 mg/dL borderline-high, greater than 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 130 mg/dL (2.6 mmol/L), although a newer upper limit of 70 mg/dL (1.8 mmol/L) 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. 

 

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: estimated LDL = [total cholesterol] − [total HDL] − [estimated VLDL]. VLDL can be calculated by dividing total triglycerides by five. Direct LDL measures are used when triglycerides exceed 400 mg/dL. The estimated VLDL and LDL have more error when triglycerides are above 400 mg/dL.

In the Framingham Heart Study, in subjects over 50 years of age, they found an 11% increase overall and 14% increase in cardiovascular disease 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. 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 likely to die of cancer, liver diseases, and mental diseases. This result indicates 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.

Although the vast majority of doctors and medical scientists consider that there is a link between cholesterol and atherosclerosis as discussed above, a 2014 meta-analysis concluded there is insufficient evidence to support the recommendation of high consumption of polyunsaturated fatty acids and low consumption of total saturated fats for cardiovascular health.

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, rather than a cause, of an underlying illness. A genetic defect in cholesterol synthesis causes Smith-Lemli-Opitz syndrome, which is often associated with low plasma cholesterol levels. Hyperthyroidism, or any other endocrine disturbance which causes upregulation of the LDL receptor, may result in hypocholesterolemia.

Cholesterol testing

The American Heart Association recommends testing cholesterol every 4–6 years for people aged 20 years or older. A separate set of American Heart Association guidelines issued in 2013 indicates that patients taking statin medications should have their cholesterol tested 4–12 weeks after their first dose and then every 3–12 months thereafter.

A blood sample after 12-hour fasting is taken by a doctor, or a home cholesterol-monitoring device is used to measure a lipid profile, an approach used to estimate a person's lipoproteins, the vastly more important issue because lipoproteins have always been concordant with outcomes though the lipid profile is commonly discordant LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study. 

The lipid profile measures: (a) total cholesterol, (b) cholesterol associated with HDL (i.e. Higher Density {than water} Lipids-transported-within-proteins) particles ("which can regress arterial disease"), (c) triglycerides and (d) (by a calculation and assumptions) cholesterol carried by LDL (i.e. Lower Density {than water} Lipids-transported-within-proteins) particles ("which drive arterial disease"). 

It is recommended to test cholesterol at least every five years if a person has total cholesterol of 5.2 mmol/L or more (200+ mg/dL), or if a man over age 45 or a woman over age 50 has HDL-C values less than 1 mmol/L (40 mg/dL), or there are other drivers heart disease and stroke. Additional drivers of heart disease include diabetes mellitus, hypertension (or use of anti-hypertensive medication), low HDL level, family history of coronary artery disease (CAD) and hypercholesterolemia, and cigarette smoking.

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 it changes colour when its temperature changes. This makes cholesterol derivatives useful for indicating temperature in liquid-crystal display thermometers and in temperature-sensitive paints.

Stereoisomers

Cholesterol has 256 stereoisomers that arise from its 8 stereocenters, although only two of the stereoisomers are of biochemical significance (nat-cholesterol and ent-cholesterol, for natural and enantiomer, respectively), and only one occurs naturally (nat-cholesterol).