High-density lipoprotein

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins, which, in order of molecular size, largest to smallest, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL. Lipoprotein molecules enable the transportation of lipids (fats), such as cholesterol, phospholipids, and triglycerides, within the water around cells (extracellular fluid), 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, the 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 tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) 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 (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 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 (PLTP).

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 (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 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 (TLF), 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 (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.

Subfractions
Five subfractions of HDL have been identified. From largest (and most effective in cholesterol removal) to smallest (and least effective), the types are 2a, 2b, 3a, 3b, and 3c.

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 study confirm the fact that HDL has a buffering role in balancing the effects of hypercoagulable state in type 2 diabetics and decreases high risk of cardiovascular complications in these patients. Also, the results obtained in this study revealed that there was negative significant correlation between HDL and Activated Partial Thromboplastin Time (APTT).

Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular diseases 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.

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 (HDL-2C, HDL-3C) 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 also risk factor for cardiovascular 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 disease and improve 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, 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.

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 exercise
 * Weight loss
 * niacin (vitamin B3, aka nicotinic acid) supplementation
 * Smoking cessation
 * Removal of trans fatty acids from the diet
 * 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
 * Decreased intake of simple carbohydrates.
 * Consumption of medium-chain triglycerides (MCTs) such as caproic acid, caprylic acid, capric acid, and lauric acid.

Consumption of cannabis (or marijuana) 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 (P=0.78) [the mean (standard error) HDL-C values in control subjects(never used), past users and current users were 53.4 (0.4), 53.9 (0.6) and 53.9 (0.7) 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 (vitamin B3) as described below (lowered LDL and increased HDL) 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 (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 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, it has little or no effect in raising HDL cholesterol. 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.