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Ldl

 

Ldl

"LDL" redirects here. For other uses, see LDL (disambiguation).

Low-density lipoprotein (LDL) 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), LDL, and high-density lipoprotein (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. Studies have shown that higher levels of type-B LDL particles (as opposed to type-A LDL particles) are associated with health problems, including cardiovascular disease.

Although the nickname is overly simplistic and thus misleading, LDL molecules are often informally called bad cholesterol because they can transport their content of many fat molecules into artery walls, attract macrophages, and thus drive atherosclerosis. In contrast, HDL molecules are frequently referred to as good cholesterol or healthy cholesterol, because they can remove fat molecules from macrophages in the wall of arteries.[1]

Testing

Blood tests typically report LDL-C, the amount of cholesterol contained in LDL. In clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low density lipoproteins are driving progression of atherosclerosis.

Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and being available from only a couple of laboratories in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.[2]

Biochemistry

Structure

Each native LDL particle enables emulsification, i.e surrounding/packaging all fatty acids being carried, enabling these fats to move around the body within the water outside cells. Each particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and hundreds to thousands (about 1500 commonly cited as an average) esterified and non-esterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) in diameter and have a mass of about 3 million daltons. Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size.[3] Determining the structure of LDL has been a tough task because of its heterogeneous structure. The structure of LDL at human body temperature in native condition, with a resolution of about 16 Angstroms using cryo-electron microscopy, has been recently described.[4]

LDL subtype patterns

LDL particles vary in size and density, and studies have shown that a pattern that has more small dense LDL particles, called Pattern B, equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less-dense LDL particles (Pattern A). This is thought to be because the smaller particles are more easily able to penetrate the endothelium. Pattern I, for intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm). According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A.[5]

Some in the medical community have suggested the correspondence between Pattern B and CHD is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test is used more often.[6]

There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense LDL.[7][8]

With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy,[9] research studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured particle concentrations.

Transport into the cell

When a cell requires additional cholesterol (beyond its current internal HMGCoA production pathway), it synthesizes the necessary LDL receptors, and inserts them into the plasma membrane. The LDL receptors diffuse freely until they associate with clathrin-coated pits. LDL particles in the bloodstream bind to these extracellular LDL receptors. The clathrin-coated pits then form vesicles that are endocytosed into the cell.

After the clathrin coat is shed, the vesicles deliver the LDL and their receptors to early endosomes, onto late endosomes to lysosomes. Here the cholesterol esters in the LDL are hydrolysed. The LDL receptors are recycled back to the plasma membrane.

Medical relevance - Atherosclerosis

Because LDL particles can also transport cholesterol into the artery wall, retained there by arterial proteoglycans and attract macrophages that engulf the LDL particles and start the formation of plaques, increased levels are associated with atherosclerosis. Over time vulnerable plaques rupture, activate blood clotting and produce arterial stenosis, which if severe enough results in heart attack, stroke, and peripheral vascular disease symptoms and major debilitating events.

Increasing evidence has revealed that the concentration and size of the LDL particles more powerfully relates to the degree of atherosclerosis progression than the concentration of cholesterol contained within all the LDL particles.[7], illustrate the sequence of events and why, though the underlying process develops over decades, the symptoms are often of sudden onset.

LDL particles are formed as [8].

A hereditary form of high LDL is familial hypercholesterolemia (FH). Increased LDL is termed hyperlipoproteinemia type II (after the dated Fredrickson classification).

LDL particles pose a risk for free radicals in the endothelium.

Role in the innate immune system

LDL lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding Apolipoprotein B, to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.[11]

Lowering LDL

Markers indicating a need for LDL Reduction
If the patient's cardiac risk is... then the patient should consider LDL reduction if the count in mg/dL is over... and LDL reduction is indicated if the count in mg/dL is over...
High, meaning a 20% or greater risk of heart attack within 10 years, or an extreme risk factor 70[12] 100[12]
moderately high, meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors 100[12] 130[12]
moderate, meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors 130[12] 160[12]
low, meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors 160[12] 190[12]

The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and present in every animal cell.

Also keep in mind that LDL particles carry many fat molecules; cholesterol, triglycerides, phospholipids and others. Thus even if the hundreds to thousands of cholesterol molecules within an average LDL particle were measured, this does not reflect the other fat molecules or even the number of LDL particles.

Pharmaceutical

  • Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the blood.
  • Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.[13]
  • PCSK9 inhibitors, in phase 3 clinical trials, by several companies, appear to be far more effective for LDL reduction than the statins, even statins at high dose.
  • Niacin (B3), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74[14] and HM74A or GPR109A.[15]
  • Several CETP inhibitors have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo.
  • [10] have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
  • Some Tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.[17] As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.
  • Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy.[18] Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.[19] However, plant sterols and stanols, if absorbed (intestinal cells generally block), greatly accelerate progression of atherosclerosis more than cholesterol delivered into the arterial walls by lipoprotein particles.
  • Insulin induces HMG-CoA reductase activity, whereas glucagon diminishes HMG-CoA reductase activity.[20] While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the digestion of carbohydrates into glucose and subsequent increase in serum glucose levels. In non-diabetics, glucagon levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.
  • A ketogenic diet may have similar response to taking niacin (lowered LDL and increased HDL) through beta-hydroxybutyrate, a ketone body, coupling the niacin receptor (HM74A).[15]
  • Lowering the blood lipid concentration of triglycerides helps lower the concentration of small LDL particles, because fat rich VLDL particles convert in the bloodstream into Small LDL particles.

Dietary

  • While eating a diet rich in plant foods and low in animal-derived foods such as meats, eggs, and dairy products has long been promoted to lower LDL levels in all patients, since plants naturally contain no cholesterol. This approach has also correlated with increasing rates of obesity, Diabetes Mellitus, and increased LDL particle concentrations. This low saturated fat/cholesterol food theory was first promoted by Ancel Keys, PhD,[21] who was later accepted to the board of the American Heart Association based on highly selected population observational data, not clinical trials, leaving out a lot of contradictory data and no examination of carbohydrate or protein intake eating patterns. Dr. Keys low fat theory was formally promoted by McGovern's report [22] as formal US government and USDA policy but has also correlated with increasing rates of obesity, Diabetes Mellitus, higher LDL particle concentrations with lower HDL particle concentrations.
  • While all animal cell membranes contain cholesterol as a building block, thus manufacture cholesterol, cholesterol in food, especially if esterified, is poorly to non-absorbed by human intestinal cells. The dominant cholesterol absorbed by the intestinal ABCA transporter protein complex is free cholesterol. The dominant origin of this free cholesterol is cholesterol manufactured within the body and excreted by the liver into the bile. Thus low cholesterol diets typically have little to no significant effects on blood cholesterol values.
  • The most effective approach has been minimizing fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body fat. Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of Diabetes Mellitus.

Importance of antioxidants

Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals,[23] it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.[24][25] Studies have reported the benefits of green tea in helping to reduce LDL; some studies have focused on the antioxidant qualities of the unfermented green tea leaves,[26] others looked at green-tea compounds called catechins which are thought to decrease cholesterol absorption in the gut.[27]

Estimation of LDL particles via cholesterol content

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available.

The lipid profile does not measure LDL particles directly but instead estimates them using the Friedewald equation[8][28] by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:

L \approx C - H - kT
where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides, and k is 0.20 if the quantities are measured in mg/dl and 0.45 if in mmol/l.

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate.[29] If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dl, may be used

L = C - H - 0.16T

This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer.

However, the concentration of LDL particles, and to a lesser extent their size, has a slightly stronger correlation with individual clinical outcome than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles [11]. It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is used to predict cardiovascular events, many other correlates of these clinical outcomes, such as diabetes mellitus, obesity and smoking, loose most of their predictive accuracy.

Normal ranges

In the USA, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were:[30][31][32]

Level mg/dL Level mmol/L Interpretation
25 to <50 <1.3 Optimal LDL cholesterol, levels in healthy young children before onset of atherosclerotic plaque in heart artery walls
<70 <1.8 Optimal LDL cholesterol, corresponding to lower rates of progression, promoted as a target option for those known to clearly have advanced symptomatic cardiovascular disease
<100 <2.6 Optimal LDL cholesterol, corresponding to lower, but not zero, rates for symptomatic cardiovascular disease events
100 to 129 2.6 to 3.3 Near optimal LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events
130 to 159 3.3 to 4.1 Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events
160 to 199 4.1 to 4.9 High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events
>200 >4.9 Very high LDL level, corresponding to highest increased rates of symptomatic cardiovascular disease events

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double blind, randomized clinical trial of men with hypercholesterolemia;[33] far more effective than coronary angioplasty/stenting or bypass surgery [34]

For instance, for people with known atherosclerosis diseases, the 2004 updated American Heart Association, NIH and NCEP recommendations are for LDL levels to be lowered to less than 70 mg/dL, unspecified how much lower. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and in secondary prevention as a 'reasonable further reduction'. Lack of evidence for such a recommendation is discussed in an article in the Annals of internal medicine.[35] It should also be noted that statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels.

It has been estimated from the results of multiple human pharmacologic LDL lowering trials that LDL should be lowered to about 50 to reduce cardiovascular event rates to near zero. For reference, from longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthood, it has been discovered that the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured Low Density Lipoprotein concentrations, the accurate approach.

The feasibility of these figures has been questioned by sceptics, claiming that many members of the AHA and NIH are heavily associated with pharmaceutical companies giving them bias towards lowering cholesterol levels and such guidelines giving rise to increased use of cholesterol lowering medicine such as statins.

A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased

Moreover, there are publications[37] regarding the risks of low-LDL cholesterol too.

Direct measurement of LDL particle concentrations

There are several competing methods for measurement of lipoprotein particle size although the evidence in favor of their superiority to existing methods is weak, even by the statements of proponents.[38] Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement,[39] as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is not widely available and is more expensive (about $98.00 US without insurance coverage) than existing tests. Furthermore the authors also said it is "...unclear whether LDL particle size measurements add value to measurement of LDL particle concentration." Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $100 US (including shipping) versus the previous costs of >$400 to >$5,000] and high accuracy. There are also other (less expensive) homogeneous assays for LDL, however most only estimate LDL.

Using NMR, as pioneered by researcher

Optimal ranges

The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of 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.

MESA Percentile LDL particles nmol/L Interpretation
0–20% <1,000 Those with lowest rate of cardiovascular disease events & low (optimal) LDL particle concentration
20–50% 1,000–1,299 Those with moderate rate of cardiovascular disease events & moderate LDL particle concentration
50–80% 1,300–1,599 Those with Borderline-High rate of cardiovascular disease events & higher LDL particle concentration
89–95% 1,600–2,000 Those with High rate of cardiovascular disease events and even higher LDL particle concentration
>95% >2,000 Those with very high rate of cardiovascular disease events and highest LDL particle concentration

The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, total and large HDL particle concentrations, along with 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.

See also

Footnotes

External links

  • The Proteolysis Map-animation
  • Adult Treatment Panel III Full Report
  • ATP III Update 2004
  • Roland Stocker

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