High density lipoprotein
Encyclopedia
High-density lipoprotein (HDL) is one of the five major groups of lipoprotein
s, which, in order of sizes, largest to smallest, are chylomicron
s, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol
and triglycerides to be transported within the water-based blood
stream. In healthy individuals, about thirty percent of blood cholesterol is carried by HDL.
Blood tests typically report HDL-C level, i.e. the amount of cholesterol contained in HDL particles. It is often contrasted with low-density or LDL cholesterol or LDL-C. HDL particles are able to remove cholesterol from within artery
atheroma
and transport it back to the liver for excretion or re-utilization, which is the main reason why the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol" (despite the fact that it is exactly the same as the cholesterol in LDL particles). Those with higher levels of HDL-C seem to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. While higher HDL levels are correlated with cardiovascular health, no incremental increase in HDL has been proven to improve health. In other words, while high HDL levels might correlate with better cardiovascular health, specifically increasing one's HDL might not increase cardiovascular health. Additionally, those few individuals producing an abnormal, apparently more efficient, HDL ApoA1 protein variant called ApoA-1 Milano
, have low measured HDL-C levels yet very low rates of cardiovascular events even with high blood cholesterol values.
particles. They are the densest because they contain the highest proportion of protein
to cholesterol
. Their most abundant apolipoprotein
s are apo A-I
and apo A-II
. The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1)
. A plasma
enzyme called lecithin-cholesterol acyltransferase
(LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, for example by the interaction with the ABCG1 transporter
and the phospholipid transport protein (PLTP)
.
HDL transports cholesterol mostly to the liver
or steroidogenic organs such as adrenals, ovary
, and testes by direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI
(SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL. As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor
pathway. The triglycerides are not stable in HDL, but degraded by hepatic lipase
so that finally small HDL particles are left, which restart the uptake of cholesterol from cells.
The cholesterol delivered to the liver is excreted into the bile
and, hence, intestine
either directly or indirectly after conversion into bile acid
s. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormone
s.
Several steps in the metabolism of HDL can contribute to the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport
and is considered as the classical protective function of HDL toward atherosclerosis.
However, HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and their protein and lipid constituents help to inhibit oxidation, inflammation
, activation of the endothelium
, coagulation
, and platelet aggregation
. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known what are the most important.
In the stress response
, serum amyloid A
, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokine
s (IL-1, IL-6
), and cortisol
produced in the adrenal cortex
and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis
.
It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles. This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either electrophoresis
(the original method developed in the 1970s) or newer NMR spectroscopy
methods (See also: NMR
and spectroscopy
), developed in the 1990s.
heart disease. Alcohol consumption tends to raise HDL levels, and moderate alcohol consumption is associated with lower cardiovascular and all-cause mortality.
Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular disease
s such as ischemic stroke
and myocardial infarction
. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk for atherosclerotic diseases.
Data from the landmark Framingham Heart Study
showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.
Even people with very low LDL levels are exposed to increased risk if their HDL levels are not high enough.
can be used.
Subfractions (HDL-2C, HDL-3C) can be measured and have clinical significance.
, NIH and NCEP
provides a set of guidelines for fasting HDL levels and risk for heart disease
.
and improve treatment methods.
and apo A-II
, positioned, back to back. Charged amino acids on the outer surface attract water, making the particles both water-soluble (so as to carry fats within the blood) and able to associate with HDL receptors on in the surface of cells, e.g. the macrophage
s of which plaque
is predominantly composed, at least in the early stages. Cholesterol is carried within and between the two particles. If the particles pick up more cholesterol, then the particles enlarge and a third or fourth apo A protein joins the grouping, termed large HDL. Chemical measurements can be used to estimate HDL concentrations present in a blood sample, though such measurements may not indicate how well the HDL particles are functioning to reverse transport cholesterol from tissues. HDL-cholesterol is measured by first removing LDL particles by aggregation or precipitation with divalent ions (such as Mg++) and then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.
measurements have been utilized since the 1960s to both indicate the number of HDL particles and additionally sort them by size. Larger HDL particles are carrying more cholesterol.
fingerprinting of the particles to measure both concentration and sizes. This methodology has reduced costs relative to ultracentrifugation.
Total HDL particle Table
Large (protective) HDL particle Table
The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles, the top quarter (>75%), and the highest concentrations of large HDL particle concentrations. Multiple other measures, including LDL particle concentrations, small LDL particle concentrations, along with VLDL concentrations, estimations of Insulin resistance
pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.
Most saturated fats increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol. A high-fat, adequate-protein, low-carbohydrate ketogenic diet
may have similar response to taking niacin as described below (lowered LDL and increased HDL) through beta-hydroxybutyrate
coupling the Niacin receptor 1.
Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrate
s and niacin
. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids. Similarly, increased HDL levels from niacin have not been shown to be efficacious in reducing cardiovascular disease in a randomized controlled trial
.
Niacin
(vitamin B3), increases HDL by selectively inhibiting hepatic Diacylglycerol acyltransferase 2, reducing triglyceride
synthesis and VLDL secretion through a receptor HM74 otherwise known as Niacin receptor 2 and HM74A / GPR109A, Niacin receptor 1.
Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. However, niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush
", do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. Both fibrates and niacin increase artery toxic homocysteine
, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, however multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates. A 2011 niacin study was halted early because patients showed no increase in heart health, but did experience an increase in the risk of stroke.
In contrast, while the use of statins is effective against high levels of LDL cholesterol, it has little or no effect in raising HDL cholesterol.
Magnesium
supplements raise HDL-C.
Apo-A1 Milano, the most effective proven HDL agent, is in commercial production by a Canadian company, Sembiosys, but as of 2010 may still be several years away from clinical availability.
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s, which, in order of sizes, largest to smallest, are chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
s, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and triglycerides to be transported within the water-based blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream. In healthy individuals, about thirty percent of blood cholesterol is carried by HDL.
Blood tests typically report HDL-C level, i.e. the amount of cholesterol contained in HDL particles. It is often contrasted with low-density or LDL cholesterol or LDL-C. HDL particles are able to remove cholesterol from within artery
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
atheroma
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of macrophage cells, or debris, that contain lipids , calcium and a variable amount of fibrous connective tissue...
and transport it back to the liver for excretion or re-utilization, which is the main reason why the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol" (despite the fact that it is exactly the same as the cholesterol in LDL particles). Those with higher levels of HDL-C seem to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. While higher HDL levels are correlated with cardiovascular health, no incremental increase in HDL has been proven to improve health. In other words, while high HDL levels might correlate with better cardiovascular health, specifically increasing one's HDL might not increase cardiovascular health. Additionally, those few individuals producing an abnormal, apparently more efficient, HDL ApoA1 protein variant called ApoA-1 Milano
ApoA-1 Milano
ApoA-1 Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr...
, have low measured HDL-C levels yet very low rates of cardiovascular events even with high blood cholesterol values.
Structure and function
HDL is the smallest of the lipoproteinLipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
particles. They are the densest because they contain the highest proportion of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
to cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. Their most abundant apolipoprotein
Apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
s are apo A-I
Apolipoprotein A1
Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism.Apolipoprotein A-I is the major protein component of high density lipoprotein in plasma. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly...
and apo A-II
Apolipoprotein A2
Apolipoprotein A2 is an apolipoprotein found in high density lipoprotein cholesterol in plasma.It has an approximate molecular weight 17 KDa....
. The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1)
ABCA1
ATP-binding cassette transporter ABCA1 , also known as the cholesterol efflux regulatory protein is a protein which in humans is encoded by the ABCA1 gene...
. A plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
enzyme called lecithin-cholesterol acyltransferase
Lecithin-cholesterol acyltransferase
Lecithin-cholesterol acyltransferase is an enzyme that converts free cholesterol into cholesteryl ester , which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become...
(LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, for example by the interaction with the ABCG1 transporter
ABCG1
ATP-binding cassette sub-family G member 1 is a protein that in humans is encoded by the ABCG1 gene. It is a homolog of the well-known Drosophila gene white.- External links :...
and the phospholipid transport protein (PLTP)
PLTP
Phospholipid transfer protein is a protein that in humans is encoded by the PLTP gene.- Function :The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to high density...
.
HDL transports cholesterol mostly to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
or steroidogenic organs such as adrenals, ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, and testes by direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI
SCARB1
Scavenger receptor class B member 1 also known as SR-BI is a protein that in humans is encoded by the SCARB1 gene. SR-BI functions as a receptor for high-density lipoprotein....
(SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL. As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
pathway. The triglycerides are not stable in HDL, but degraded by hepatic lipase
Hepatic lipase
Hepatic lipase is a form of lipase. It is expressed in the liver and adrenal glands.One of the principal functions of hepatic lipase is to convert IDL to LDL.-Clinical significance:...
so that finally small HDL particles are left, which restart the uptake of cholesterol from cells.
The cholesterol delivered to the liver is excreted into the bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
and, hence, intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
either directly or indirectly after conversion into bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
s. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormone
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
s.
Reverse cholesterol transport
Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma....
and is considered as the classical protective function of HDL toward atherosclerosis.
However, HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and their protein and lipid constituents help to inhibit oxidation, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, activation of the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
, and platelet aggregation
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known what are the most important.
In the stress response
Fight-or-flight response
The fight-or-flight response was first described by Walter Bradford Cannon....
, serum amyloid A
Serum amyloid A
Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli . These proteins are produced predominantly by the liver...
, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s (IL-1, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
), and cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
produced in the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
.
It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles. This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
(the original method developed in the 1970s) or newer NMR spectroscopy
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy, is a research technique that exploits the magnetic properties of certain atomic nuclei to determine physical and chemical properties of atoms or the molecules in which they are contained...
methods (See also: NMR
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
and spectroscopy
Spectroscopy
Spectroscopy is the study of the interaction between matter and radiated energy. Historically, spectroscopy originated through the study of visible light dispersed according to its wavelength, e.g., by a prism. Later the concept was expanded greatly to comprise any interaction with radiative...
), developed in the 1990s.
Epidemiology
Men tend to have noticeably lower HDL levels, with smaller size and lower cholesterol content, than women. Men also have an increased incidence of atheroscleroticAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
heart disease. Alcohol consumption tends to raise HDL levels, and moderate alcohol consumption is associated with lower cardiovascular and all-cause mortality.
Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
s such as ischemic stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk for atherosclerotic diseases.
Data from the landmark Framingham Heart Study
Framingham Heart Study
The Framingham Heart Study is a long-term, ongoing cardiovascular study on residents of the town of Framingham, Massachusetts. The study began in 1948 with 5,209 adult subjects from Framingham, and is now on its third generation of participants...
showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.
Even people with very low LDL levels are exposed to increased risk if their HDL levels are not high enough.
Estimating HDL via associated cholesterol
Many laboratories used a two-step method: Chemical precipitation of lipoproteins containing apoprotein B, then calculating HDL associated cholesterol as the cholesterol remaining in the supernate, and there are also direct methods. Both methods have long been promoted on the basis of lowest cost, though neither of these measurements directly, or reliably, reflects HDL particle functionality to remove cholesterol from atherosclerotic plaque and can therefore be misleading, especially on an individual patient-by-patient basis Labs use the routine dextran sulfate-Mg2+ precipitation method with ultracentrifugation/dextran sulfate-Mg2+ precipitation as reference method. HPLCHigh-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
can be used.
Subfractions (HDL-2C, HDL-3C) can be measured and have clinical significance.
Recommended ranges
The American Heart AssociationAmerican Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
, NIH and NCEP
National Cholesterol Education Program
The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia in the United States of America...
provides a set of guidelines for fasting HDL levels and risk for heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
.
| Level mg/dL Gram per litre A gram per liter or litre is a unit of measurement of mass concentration that shows how many grams of a certain substance are present in one litre of a usually liquid or gaseous mixture. It is not an SI unit because it contains the non-SI unit litre... |
Level mmol Mole (unit) The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value... /L Litre pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre... |
Interpretation |
| <40 for men, <50 for women | <1.03 | Low HDL cholesterol, heightened risk for heart disease |
| 40–59 | 1.03–1.55 | Medium HDL level |
| >60 | >1.55 | High HDL level, optimal condition considered protective against heart disease |
Measuring HDL concentration and sizes
As technology has reduced costs and clinical trial have continued to demonstrate the importance of HDL, methods for directly measuring HDL concentrations, and size (which indicates function) at lower costs have become increasingly available and regarded as more important for assessing individual risk for progressive arterial diseaseAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
and improve treatment methods.
Chemical measurements
HDL, as discussed above, forms from two large proteins, predominantly apo A-IApolipoprotein A1
Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism.Apolipoprotein A-I is the major protein component of high density lipoprotein in plasma. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly...
and apo A-II
Apolipoprotein A2
Apolipoprotein A2 is an apolipoprotein found in high density lipoprotein cholesterol in plasma.It has an approximate molecular weight 17 KDa....
, positioned, back to back. Charged amino acids on the outer surface attract water, making the particles both water-soluble (so as to carry fats within the blood) and able to associate with HDL receptors on in the surface of cells, e.g. the macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s of which plaque
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
is predominantly composed, at least in the early stages. Cholesterol is carried within and between the two particles. If the particles pick up more cholesterol, then the particles enlarge and a third or fourth apo A protein joins the grouping, termed large HDL. Chemical measurements can be used to estimate HDL concentrations present in a blood sample, though such measurements may not indicate how well the HDL particles are functioning to reverse transport cholesterol from tissues. HDL-cholesterol is measured by first removing LDL particles by aggregation or precipitation with divalent ions (such as Mg++) and then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.
Electrophoresis measurements
Since the HDL particles have a net negative charge and vary by size, electrophoresisElectrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
measurements have been utilized since the 1960s to both indicate the number of HDL particles and additionally sort them by size. Larger HDL particles are carrying more cholesterol.
NMR measurements
The newest methodology for measuring HDL particles, available clinically since the late 1990s http://www.liposcience.com/index2.cfm?scid1=72&id=28 uses Nuclear Magnetic ResonanceNuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
fingerprinting of the particles to measure both concentration and sizes. This methodology has reduced costs relative to ultracentrifugation.
Optimal Total and Large HDL concentrations
The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA http://www.mesa-nhlbi.org trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.Total HDL particle Table
| MESA Percentile | Total HDL particles μmol Mole (unit) The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value... /L |
Interpretation |
|---|---|---|
| >75% | >34.9 | Those with highest (Optimal) total HDL particle concentrations & lowest rates of cardiovascular disease events |
| 50–75% | 30.5–34.5 | Those with moderately high total HDL particle concentrations & moderate rates of cardiovascular disease events |
| 25–50% | 26.7–30.5 | Those with lower total HDL particle concentrations & Borderline-High rates of cardiovascular disease |
| 0–25% | <26.7 | Those with lowest total HDL particle concentrations & Highest rates of cardiovascular disease events |
Large (protective) HDL particle Table
| MESA Percentile | Large HDL particles μmol Mole (unit) The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value... /L |
Interpretation |
|---|---|---|
| >75% | >7.3 | Those with highest (Optimal) Large HDL particle concentrations & lowest rates of cardiovascular disease events |
| 50–75% | 4.8–7.3 | Those with moderately high Large HDL particle concentrations & moderate rates of cardiovascular disease events |
| 25–50% | 3.1–4.8 | Those with lower Large HDL particle concentrations & Borderline-High rates of cardiovascular disease |
| 0–25% | <3.1 | Those with lowest Large HDL particle concentrations & Highest rates of cardiovascular disease events |
The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles, the top quarter (>75%), and the highest concentrations of large HDL particle concentrations. Multiple other measures, including LDL particle concentrations, small LDL particle concentrations, along with VLDL concentrations, estimations of Insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.
Memory
Fasting serum lipids have been associated with short term verbal memory. In a large sample of middle aged adults, low HDL cholesterol was associated with poor memory and decreasing levels over a five year follow-up period were associated with decline in memory.Diet and lifestyle
Certain changes in lifestyle may have a positive impact on raising HDL levels:- Aerobic exerciseAerobic exerciseAerobic exercise is physical exercise of relatively low intensity that depends primarily on the aerobic energy-generating process. Aerobic literally means "living in air", and refers to the use of oxygen to adequately meet energy demands during exercise via aerobic metabolism...
- Weight lossWeight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
- Nicotinic Acid supplementation
- Smoking cessationSmoking cessationSmoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
- Removal of trans fatty acidsTrans fatTrans fat is the common name for unsaturated fat with trans-isomer fatty acid. Because the term refers to the configuration of a double carbon-carbon bond, trans fats are sometimes monounsaturated or polyunsaturated, but never saturated....
from the diet - Mild to moderate alcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
intake - Addition of soluble fiberDietary fiberDietary fiber, dietary fibre, or sometimes roughage is the indigestible portion of plant foods having two main components:* soluble fiber that is readily fermented in the colon into gases and physiologically active byproducts, and* insoluble fiber that is metabolically inert, absorbing water as it...
to diet - Consumption of omega-3 fatty acids such as fish oil or flax oil
- Increased intake of cis-unsaturated fats and cholesterol.
Most saturated fats increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol. A high-fat, adequate-protein, low-carbohydrate ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
may have similar response to taking niacin as described below (lowered LDL and increased HDL) through beta-hydroxybutyrate
Beta-hydroxybutyrate
beta-Hydroxybutyric acid is a ketone body. It is a chiral compound having two enantiomers, D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. Like the other ketone bodies , levels of beta-hydroxybutyrate are raised in ketosis...
coupling the Niacin receptor 1.
Drugs
While higher HDL levels are correlated with cardiovascular health, no incremental increase in HDL has been proven to improve health. In other words, while high HDL levels might correlate with better cardiovascular health, specifically increasing one's HDL might not increase cardiovascular health.Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrate
Fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...
s and niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids. Similarly, increased HDL levels from niacin have not been shown to be efficacious in reducing cardiovascular disease in a randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
.
Niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
(vitamin B3), increases HDL by selectively inhibiting hepatic Diacylglycerol acyltransferase 2, reducing triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
synthesis and VLDL secretion through a receptor HM74 otherwise known as Niacin receptor 2 and HM74A / GPR109A, Niacin receptor 1.
Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. However, niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
", do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. Both fibrates and niacin increase artery toxic homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, however multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates. A 2011 niacin study was halted early because patients showed no increase in heart health, but did experience an increase in the risk of stroke.
In contrast, while the use of statins is effective against high levels of LDL cholesterol, it has little or no effect in raising HDL cholesterol.
Magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
supplements raise HDL-C.
Apo-A1 Milano, the most effective proven HDL agent, is in commercial production by a Canadian company, Sembiosys, but as of 2010 may still be several years away from clinical availability.
See also
- Asymmetric dimethylarginineAsymmetric dimethylarginineAsymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...
- Cardiovascular diseaseCardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
- Cholesteryl ester storage diseaseCholesteryl ester storage diseaseCholesteryl Ester Storage Disease is the late onset phenotype for Lysosomal Acid Lipase Deficiency, a Lysosomal storage disease, which also has an early onset phenotype known as Wolman disease that primarily affects infants. CESD can present in childhood but often goes unrecognized until...
- EndotheliumEndotheliumThe endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
- Lipid profileLipid profileLipid profile or lipid panel, is the collective term given to the estimation of, typically, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. An extended lipid profile may include very low-density lipoprotein...
- Low-density lipoprotein
- Lysosomal acid lipase deficiencyLysosomal Acid Lipase DeficiencyLysosomal Acid Lipase Deficiency happens when the body does not produce enough active LAL enzyme. Under normal conditions, the body produces an enzyme called lysosomal acid lipase . This enzyme plays an important role in breaking down fatty material in the body...
External links
- Adult Treatment Panel III Full Report – National Heart, Lung, and Blood Institute
- ATP III Update 2004 – National Heart, Lung, and Blood Institute
- HDL: The good, but complex, cholesterol – Harvard Heart Letter
- El hdl