High-density lipoprotein

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. 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.

Structure and function
HDL is the smallest of the lipoprotein particles. They are the densest because they contain the highest proportion of protein to cholesterol. Their 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. 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 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 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 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.

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.

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


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, reflect HDL particle functionality to remove cholesterol from atherosclerotic plaque and can therefor 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. HPLC can be used.

Subfractions (HDL-2C, HDL-3C) can be measured and have clinical significance.

Recommended ranges
The American Heart Association, NIH and NCEP provides a set of guidelines for fasting HDL levels and risk for 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 disease and improve treatment methods.

Chemical measurements
HDL, as discussed above, forms from two large proteins, predominantly apo A-I 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 macrophages 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.

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, thus presumably function. 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 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 trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

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.

Memory
Fasting serum lipids have been associated with short term verbal memory. In a large sample of middle aged adults, low HDL cholesterol were 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
 * 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 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 may have similar response to taking niacin 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 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 fibrates 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.