High-density lipoprotein(HDL) is one of the five major groups oflipoproteins.[1] Lipoproteins are complex particles composed of multiple proteins which transport allfat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle (organized by one, two or threeApoA). HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.[2]
HDL particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reducemacrophage accumulation, and thus help prevent or even regressatherosclerosis.[3]
Lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. Unlike the larger lipoprotein particles, which deliver fat molecules to cells, HDL particles remove fat molecules from cells. The lipids carried includecholesterol,phospholipids, andtriglycerides, amounts of each are variable.[4]
HDL particles remove fats and cholesterol from cells, including withinartery wallatheroma, and transport it back to the liver for excretion or re-use. Increasing concentrations of HDL particles in the blood are associated with decreasing accumulation ofatherosclerosis within the walls of arteries,[5] reducing the risk ofsudden plaque ruptures,cardiovascular disease,stroke and othervascular diseases.[2] People with higher levels of HDL-C tend to have fewer problems withcardiovascular diseases, while those with low HDL-C levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease.[6][needs update] Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.[7][needs update]
However, a higher blood level of HDL is not necessarily protective against cardiovascular disease and may even be harmful in extremely high quantities,[8] with an increased cardiovascular risk, especially in hypertensive patients.[9]
Because of the high cost of directly measuring HDL particles,blood tests commonly measure a surrogate value, HDL-cholesterol (HDL-C), i.e. the cholesterol associated with HDL particles. HDL-C is often contrasted with the amount of cholesterol estimated to be carried withinlow-density lipoprotein particles, known as LDL-C, with HDL-C being nicknamed "good cholesterol" and LDL-C "bad cholesterol".
In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by HDL.[3] 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 withinartery wallatheroma, and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol". Those with higher levels of HDL-C tend to have fewer problems withcardiovascular 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.[10][needs update] Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.[11][needs update]
The remainder of the serum cholesterol after subtracting the HDL is thenon-HDL cholesterol. The concentration of these other components, which may causeatheroma, is known as thenon-HDL-C. This is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated.[12]
With a size ranging from 5 to 17 nm, HDL is the smallest of thelipoprotein particles.[2] It is the densest because it contains the highest proportion ofprotein tolipids.[2] Its most abundantapolipoproteins areapo A-I andapo A-II. A rare genetic variant,ApoA-1 Milano, has been documented to be far more effective in both protecting against and regressing arterial disease,atherosclerosis.
The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles,[2] whose NMR structure was published;[13] the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with theATP-binding cassette transporter A1 (ABCA1).[14] Aplasma enzyme calledlecithin-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 blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with theABCG1 transporter and thephospholipid transport protein (PLTP).[2]
HDL transports cholesterol mostly to theliver orsteroidogenic organs such asadrenals,ovary, andtestes by both direct and indirect pathways. HDL is removed by HDL receptors such asscavenger 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 bycholesteryl ester transfer protein (CETP).[2] This protein exchanges triglycerides ofVLDL against cholesteryl esters of HDL. As the result, VLDLs are processed toLDL, which are removed from the circulation by theLDL receptor pathway. The triglycerides are not stable in HDL, but are degraded byhepatic lipase so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells.[2]
The cholesterol delivered to the liver is excreted into thebile and, hence,intestine either directly or indirectly after conversion intobile acids. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis ofsteroid hormones.[2]
Several steps in the metabolism of HDL can participate in the transport of cholesterol from lipid-ladenmacrophages ofatheroscleroticarteries, termedfoam cells, to the liver for secretion into the bile. This pathway has been termedreverse cholesterol transport and is considered as the classical protective function of HDL toward atherosclerosis.
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 inhibitoxidation,inflammation,activation of the endothelium,coagulation, andplatelet 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 parasiteTrypanosoma brucei brucei. This HDL subfraction, termed trypanosome lytic factor (TLF), contains specialized proteins that, while very active, are unique to the TLF molecule.[15]
In thestress response,serum amyloid A, which is one of theacute-phase proteins and an apolipoprotein, is under the stimulation ofcytokines (interleukin 1,interleukin 6), andcortisol produced in theadrenal 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 asamyloidosis.
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.[16] This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using eitherelectrophoresis (the original method developed in the 1970s) or newerNMR spectroscopy methods (See alsonuclear magnetic resonance andspectroscopy), developed in the 1990s.
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.[17]
Men tend to have noticeably lower HDL concentrations, with smaller size and lower cholesterol content, than women. Men also have a greater incidence ofatherosclerotic heart disease. 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 andactivated partial thromboplastin time (APTT).[citation needed]
Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value againstcardiovascular diseases such as ischemic stroke andmyocardial infarction. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk foratherosclerotic diseases.[18]
Data from the landmarkFramingham 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.[19][20]
Even people with very low LDL levels achieved bystatin treatment are exposed to increased risk if their HDL levels are not high enough.[21][non-primary source needed]
Very high HDL-C levels (≥80 mg/dL in men, ≥100 mg/dL in women) appears to be detrimental to cardiovascular outcomes. Several genetic conditions cause abnormally low or high HDL-C levels, often without the expected change in cardiovascular disease rates. In fact, when many known correlates of CVD risks are controlled for, HDL-C does not have any correlation with cardiovascular event risks. In this way, HDL-C only seems to serve as an imperfect, but easy-to-measure, proxy for a healthy lifestyle. What does correlate well with CVD risks even when these factors are controlled for is a direct measure of the capability forreverse cholesterol transport in a person's blood serum, thecholesterol efflux capacity (CEC).[22]
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.[23] Most laboratories now use automated homogeneous analytical methods in which lipoproteins containingapo B are blocked using antibodies to apo B, then acolorimetric enzyme reaction measures cholesterol in the non-blocked HDL particles.[24]HPLC can also be used.[25] Subfractions (HDL-2C, HDL-3C) can be measured,[26] but clinical significance of these subfractions has not been determined.[27] The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.[citation needed]
TheAmerican Heart Association,NIH andNCEP provide a set of guidelines for fasting HDL levels and risk forheart disease.[28][29][30]
| Level mg/dL | Levelmmol/L | Interpretation |
|---|---|---|
| <40 (men), <50 (women) | <1.03 (men), <1.29 (women) | Low HDL cholesterol, considered correlated for heart disease (heightened risk) |
| 40–59 (men), 50–59 (women) | 1.03–1.55 (men), 1.29–1.55 (women) | Medium HDL level |
| >59 | >1.55 | High HDL level, optimal condition considered correlated against heart disease |
High LDL with low HDL level is an additional risk factor for cardiovascular disease.[31]
As technology has reduced costs and clinical trials have continued to demonstrate the importance of HDL,[32] methods for directly measuring HDL concentrations and size (which indicates function) at lower costs have become more widely available and increasingly regarded as important for assessing individual risk for progressivearterial disease and treatment methods.[citation needed]
Since the HDL particles have a net negative charge and vary by density & size, ultracentrifugation combined withelectrophoresis have been utilized since before 1950 to enumerate the concentration of HDL particles and sort them by size with a specific volume of blood plasma. Larger HDL particles are carrying more cholesterol.
Concentration and sizes of lipoprotein particles can be estimated usingnuclear magnetic resonance fingerprinting.[33]
The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA[34] trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.
| MESA Percentile | Total HDL particlesμmol/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 |
| MESA Percentile | Large HDL particlesμmol/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 particles. Multiple additional measures, including LDL particle concentrations, small LDL particle concentrations, VLDL concentrations, estimations ofinsulin resistance and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are routinely provided in clinical testing.
While higher HDL levels are correlated with lower risk of cardiovascular diseases, no medication used to increase HDL has been proven to improve health.[2][35] As of 2017, numerous lifestyle changes and drugs to increase HDL levels were under study.[2]
HDL lipoprotein particles that bearapolipoprotein C3 are associated with increased, rather than decreased, risk forcoronary heart disease.[36]
Certain changes in diet and exercise may have a positive impact on raising HDL levels:[37]
Mostsaturated fats increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol.[51]
HDL levels can be increased bysmoking cessation,[43] or mild to moderatealcohol intake.[52][53][54][55][56][57]
Cannabis in unadjusted analyses, past and current cannabis use was not associated with higher HDL-C levels.[58] 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].[58]
Exogenousanabolic androgenic steroids, particularly17α-alkylated anabolic steroids and others administered orally, can reduce HDL-C by 50 percent or more.[59] Otherandrogen receptor agonists such asselective androgen receptor modulators can also lower HDL. As there is some evidence that the HDL reduction is caused by increasedreverse cholesterol transport, it is unknown if AR agonists' HDL-lowering effect is pro- or anti-atherogenic.[60]
Pharmacological therapy to increase the level of HDL cholesterol includes use offibrates andniacin. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids.[61]
Niacin (nicotinic acid, a form ofvitamin B3) increases HDL by selectively inhibiting hepaticdiacylglycerol acyltransferase 2, reducingtriglyceride synthesis andVLDL secretion through a receptor HM74[62] otherwise known asniacin receptor 2 and HM74A / GPR109A,[63]niacin receptor 1.
Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,[64] making it the most powerful agent to increase HDL-cholesterol.[65][66] A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.[67] Niacin products sold as "no-flush",i.e. not having side-effects such as "niacinflush", do not, however, 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.[68] Both fibrates and niacin increase artery toxichomocysteine, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, but 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 extended-release niacin (Niaspan) 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.[69]
In contrast, while the use ofstatins is effective against high levels ofLDL cholesterol, most have little or no effect in raising HDL cholesterol.[65]Rosuvastatin andpitavastatin, however, have been demonstrated to significantly raise HDL levels.[70]
Lovaza has been shown to increase HDL-C.[71] However, the best evidence to date suggests it has no benefit for primary or secondary prevention of cardiovascular disease.
ThePPAR modulatorGW501516 has shown a positive effect on HDL-C[72] and an antiatherogenic where LDL is an issue.[73] However, research on the drug has been discontinued after it was discovered to cause rapid cancer development in several organs in rats.[74][75]
HMG CoA Reductase is an important enzyme in lipid and cholesterol metabolism, but it is not the only one. The statins act by inhibiting, temporarily, the enzyme, in a dose response relationship whereas the magnesium ion (Mg2+) is an important part of a complex control and regulation of this important pathway. Both lower LDL-C, some statins can raise HDL-C and lower triglycerides, but Mg supplements do both quite reliably.
Lipids:lipoprotein particle metabolism | ||
|---|---|---|
| Lipoprotein particle classes and subclasses |
|  |
| Apolipoproteins | ||
| Extracellularenzymes | ||
| Lipid transfer proteins | ||
| Cell surface receptors | ||
| ATP-binding cassette transporter | ||
