High-density lipoprotein is one of the five major groups of lipoproteins, which, in order
of molecular size, largest to smallest, are chylomicrons, very low-density lipoprotein,
intermediate-density lipoprotein, low-density lipoprotein, and HDL.
Lipoprotein molecules enable the transportation of lipids, such as cholesterol, phospholipids,
and triglycerides, within the water around cells, including the bloodstream.
Because of the high cost of directly measuring HDL and LDL protein particles, blood tests
are commonly performed for the surrogate value, HDL-C, i.e. the cholesterol associated with
ApoA-1/HDL particles.
In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried
by HDL.
This is often contrasted with the amount of cholesterol estimated to be carried within
low-density lipoprotein particles, LDL, and called LDL-C. HDL particles remove fats and
cholesterol from cells, including within artery wall atheroma, and transport it back to the
liver for excretion or re-utilization; thus the cholesterol carried within HDL particles
is sometimes called "good cholesterol".
Those with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases,
while those with low HDL-C cholesterol levels have increased rates for heart disease.
Higher native HDL levels are correlated with better cardiovascular health; however, it
does not appear that further increasing one's HDL improves cardiovascular outcomes.
Structure and function HDL is the smallest of the lipoprotein particles.
It is the densest because it contains the highest proportion of protein to lipids.
Its most abundant apolipoproteins 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; the complexes
are capable of picking up cholesterol, carried internally, from cells by interaction with
the ATP-binding cassette transporter A1.
A plasma enzyme called lecithin-cholesterol acyltransferase converts the free cholesterol
into cholesteryl ester, which is then sequestered into the core of the lipoprotein particle,
eventually causing the newly synthesized HDL to assume a spherical shape.
HDL particles 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.
HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals,
ovary, and testes by both direct and indirect pathways.
HDL is removed by HDL receptors such as scavenger receptor 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.
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 are 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 acids.
Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis
of steroid hormones.
Several steps in the metabolism of HDL can participate in 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 its 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 which are the most important.
In addition, a small subfraction of HDL lends protection against the protozoan parasite
Trypanosoma brucei brucei.
This HDL subfraction, termed trypanosome lytic factor, contains specialized proteins that,
while very active, are unique to the TLF molecule.
In the stress response, serum amyloid A, which is one of the acute-phase proteins and an
apolipoprotein, is under the stimulation of cytokines, 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 or newer NMR spectroscopy
methods, developed in the 1990s.
Subfractions Five subfractions of HDL have been identified.
From largest to smallest, the types are 2a, 2b, 3a, 3b, and 3c.
Major Lipids in body The lipids are a heterogeneous group of compounds which are relatively insoluble
in water and soluble in non polar solvents.
TC, TG, and phospholipids are the major lipids in the body.
They are transpoted as complexes of lipid and proteins known as lipoproteins.
TGs: TGs are formed by combining glycerol with three molecules of fatty acid.
TGs, as major components of VLDL and chylomicrons, play an important role in metabolism.When
the body requers fatty acids as an energy source, the hormone glucagon signals the breakdown
of the TGs by lipase to release free fatty acids.
TGs are water insoluble, non-polar neutral fats.
These are not the structural components of biological membranes.TGs synthesis and storage
mostly occurs in liver and adipose tissue.
FFA and glycerol must be activated prior to the synthesis of TGs into acylCoA glycerol
-3-phosphate respectively.
Cholesterol: The name cholesterol originates from the Greek chole- andstereos, and the
chemical suffix-ol for an alcohol.
It is an essential structural component of cell membrane, where it is required to establish
proper membrane permeability and fluidity.
In addition, cholesterol is an important component for the manufacture of bile acids, steroid
hormones, and vitamin D. Although cholesterol is an important and necessary molecule, a
high level of serum cholesterol is an indicator for diseases such as heart disease.
About 20-25% of total daily cholesterol production occurs in the liver.
Phospholipids: Phospholipids are TGs that are covalently bonded to aphosphate group
by an ester linkage.
Phospholipids perform important functions including regulating membrane permeability
and in maintaining electron transport chain in mitochondria.
They participate in the reverse cholesterol transport and thus help in the removal of
cholesterol from the body.
They are involved in signal transmission across membranes and they act as detergents and help
in solubilization of cholesterol.
Lipoprotein: These contists of a central core of a hydrophobic lipid encased in a hydrophilic
coat of polar phospholipid, free cholesterol and apolipoprotein.
There are four main goals of lipoprotein, differing in the relative proportion of the
core lipids and in the type of apoprotein.
• Chylomicrons • VLDL-C particiles • IDL-C particles • LDL-C particles • HDL-C particle
• Lipoprotein [LP(a)] 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 atherosclerotic heart disease.
Alcohol consumption tends to raise HDL levels, and moderate alcohol consumption is associated
with lower cardiovascular and all-cause mortality.
Recent studies confirm the fact that HDL has a buffering role in balancing the effects
of the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular
complications in these patients.
Also, the results obtained in this study revealed that there was a significant negative correlation
between HDL and activated partial thromboplastin time.
Epidemiological studies have shown that high concentrations of HDL have protective value
against cardiovascular diseases such as ischemic stroke and myocardial infarction.
Low concentrations of HDL 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.
Estimating HDL via associated cholesterol Clinical laboratories formerly measured HDL
cholesterol by separating other lipoprotein fractions using either ultracentrifugation
or chemical precipitation with divalent ions such as Mg2+, then coupling the products of
a cholesterol oxidase reaction to an indicator reaction.
The reference method still uses a combination of these techniques.
Most laboratories now use automated homogeneous analytical methods in which lipoproteins containing
apo B are blocked using antibodies to apo B, then a colorimetric enzyme reaction measures
cholesterol in the non-blocked HDL particles.
HPLC can also be used.
Subfractions can be measured and have clinical significance.
The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but
is thought to be less accurate.
Recommended ranges The American Heart Association, NIH and NCEP
provides a set of guidelines for fasting HDL levels and risk for heart disease.
High LDL with low HDL level is an additional risk factor for cardiovascular disease.
Measuring HDL concentration and sizes As technology has reduced costs and clinical
trials have continued to demonstrate the importance of HDL, methods for directly measuring HDL
concentrations and size at lower costs have become more widely available and increasingly
regarded as important for assessing individual risk for progressive arterial disease and
treatment methods.
Electrophoresis measurements Since the HDL particles have a net negative
charge and vary by size, electrophoresis 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 uses nuclear magnetic resonance fingerprinting
of the particles to measure both concentration and sizes.
This methodology was pioneered by researcher Jim Otvos and the North Carolina State University
academic research spinoff company and dramatically reduced the cost of HDL measurements.
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 trial, a medical research study sponsored by the United States National Heart,
Lung, and Blood Institute.
The lowest incidence of atherosclerotic events over time occurs within those with both the
highest concentrations of total HDL particles and the highest concentrations of large HDL
particles.
Multiple additional measures, including LDL particle concentrations, small LDL particle
concentrations, VLDL concentrations, estimations of insulin resistance and standard cholesterol
lipid measurements are routinely provided in clinical testing.
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.
Increasing HDL levels Diet and lifestyle
Certain changes in lifestyle may have a positive impact on raising HDL levels:
Decreased intake of simple carbohydrates.
Weight loss niacin supplementation
Aerobic exercise Smoking cessation
Mild to moderate alcohol intake Addition of soluble fiber to diet
Consumption of omega-3 fatty acids such as fish oil or flax oil
Increased intake of cis-unsaturated fats Consumption of medium-chain triglycerides
such as caproic acid, caprylic acid, capric acid, and lauric acid.
Removal of trans fatty acids from the diet Consumption of cannabis has been speculated
to have a positive impact on the HDL-C level.
However, a study performed in 4635 patients demonstrated no effect on the HDL-C levels
[the mean HDL-C values in control subjects, past users and current users were 53.4, 53.9
and 53.9 mg/dL, respectively].
Most saturated fats increase HDL cholesterol to varying degrees and 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 through beta-hydroxybutyrate coupling the Niacin receptor 1.
Drugs While higher HDL levels are correlated with
cardiovascular health, no 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 fibrates
and niacin.
Fibrates have not been proven to have an effect on overall deaths from all causes, despite
their effects on lipids.
Niacin 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 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 adding niacin to their statin treatment
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, most
have little or no effect in raising HDL cholesterol.
However, several statins - rosuvastatin and pitavastatin - have been demonstrated to significantly
raise HDL levels.
As statins are associated with side effects like myopathy which causes sore muscles, patients
who experience these side effects may need to be given a lower dose of statin to control
cholesterol.
Cannabis In unadjusted analyses, past and current marijuana use were associated with
lower levels of fasting insulin, glucose, HOMA-IR, BMI, and hemoglobin A1c but either
current or past marijuana use was not associated with higher HDL-C levels.
Lovaza has been shown to increase HDL-C. However, the best evidence to date suggests it has
no benefit for primary or secondary prevention of cardiovascular disease.
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.
See also Asymmetric dimethylarginine
Cardiovascular disease Cholesteryl ester storage disease
Endothelium Lipid profile
Low-density lipoprotein Lysosomal acid lipase deficiency
References Notes
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 HDL Cholesterol at Lab Tests Online