Low-density lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of multiple different fat molecules, including cholesterol, within the water around cells and within the water-based bloodstream. Studies have shown that higher levels of type-B LDL particles (as opposed to type-A LDL particles) promote health problems and cardiovascular disease, they are often informally called the bad cholesterol particles, (as opposed to HDL particles, which are frequently referred to as good cholesterol or healthy cholesterol particles).^[1]

Contents 1 Testing 2 Biochemistry 2.1 Structure 2.2 LDL subtype patterns 2.3 Transport into the cell 3 Medical relevance 3.1 Role in the innate immune system 3.2 Lowering LDL 3.2.1 Pharmaceutical 3.2.2 Dietary 3.3 Importance of antioxidants 4 Estimation of LDL particles via cholesterol content 4.1 Normal ranges 5 Direct measurement of LDL concentration 5.1 Optimal ranges 6 See also 7 Footnotes 8 References & External Links

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 contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), which circulates the fatty acids, keeping them soluble in the aqueous environment. In addition, LDL has a highly-hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and about 1500 esterified cholesterol molecules. This core 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, but since LDL particles contain a changing number of fatty acids, they actually have a distribution of mass and size.^[3] Determining structure of LDL has been a tough task because of its heterogeneous structure. First structure of LDL at human body temperature in native condition has been recently found using cryo-electron microscopy and it has resolution of 16 Angstrom.^[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 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 to 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 commonly.

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.^[6][7]

With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy,^[8] research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively-measured particle concentrations.

Transport into the cell

When a cell requires cholesterol, 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 blood stream 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

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.^[9] The healthiest pattern A, though relatively rare, is to have small numbers of large LDL particles and no small particles. Having small LDL particles, though common, is an unhealthy pattern B; high concentrations of small LDL particles (even though potentially carrying the same total cholesterol content as a low concentration of large particles) correlates with much faster growth of atheroma, progression of atherosclerosis and earlier and more severe cardiovascular disease events and death. This video [5], examining autopsy specimens from an actual heart attack resulting in sudden death, shows the seqence. These videos, [6] and [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 VLDL lipoproteins lose triglyceride through the action of lipoprotein lipase (LPL) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters [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 cardiovascular disease when they invade the endothelium and becomes oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debries [9] and 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.^[10]

Lowering LDL

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 in the pathway.

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 powerfully reduce LDL particle concentrations when combined with statins.^[11]

• Niacin (B₃), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74^[12] and HM74A or GPR109A.^[13]

• Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.^[14] Other, more recently developed and tested fibrates, e.g. fenofibric acid [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.^[15] 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.

Dietary

• 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.

• Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy.^[16] 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.^[17]

• Insulin induces HMG-CoA reductase activity, whereas glucagon diminishes HMG-CoA reductase activity.^[18] 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).^[13]

• 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.

Importance of antioxidants

Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals,^[19] it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.^[20] Studies have reported the benefits of green tea in helping to reduce LDL. The unfermented green tea leaves contain powerful antioxidants which can lower total cholesterol besides increasing level of HDL or the good cholesterol.^[21]

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^[7][22] by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:

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.^[23] If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities are in mg/dl, may be used

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, lose much of their predictive power.

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:^[24][25][26]

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;^[27] far more effective than coronary angioplasty/stenting or bypass surgery.

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.^[28] 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 LDLipoprotein concentrations, probably not the better 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 LDL cholesterol control for diabetes relative to coronary heart disease.^[29]

Moreover, there are publications^[30] regarding the risks of low-LDL cholesterol too.

Direct measurement of LDL concentration

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.^[31] Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement,^[32] 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 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.

Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who participated in the MESA trial.^[33]

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 & even higher LDL particle concentration
>95%	>2,000	Those with Very High rate of cardiovascular disease events & 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

References & External Links

• Fat (LDL) Degradation: PMAP The Proteolysis Map-animation
• Adult Treatment Panel III Full Report
• ATP III Update 2004
• Cromwell WC, Otvos JD (September 2004). "Low-density lipoprotein particle number and risk for cardiovascular disease". Current Atherosclerosis Reports 6 (5): 381–7. doi:10.1007/s11883-004-0050-5. PMID 15296705. 
• O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). "Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal". Journal of the American College of Cardiology 43 (11): 2142–6. doi:10.1016/j.jacc.2004.03.046. PMID 15172426. 

Lipids: lipoprotein metabolism Apolipoproteins APOA (1, 2, 4, 5) · APOB · APOC (1, 2, 3, 4) · APOD · APOE · APOH SAA (SAA1) Lipoproteins Chylomicron · HDL · LDL · IDL · VLDL · Lp(a) Extracellular enzymes LCAT · LIPC · LPL Lipid transfer proteins CETP · MTTP · PLTP Cell surface receptors HDL: SCARB1 IDL: LRP (LRP1 · LRP1B · LRP2 · LRP3 · LRP4 · LRP5 · LRP5L · LRP6 · LRP8 · LRP10 · LRP11 · LRP12) LDL: LDLR · LRPAP1 ATP-binding cassette transporter ABCA1 · ABCG5 · ABCG8 M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

Cardiovascular disease: vascular disease · Circulatory system pathology (I70–I99, 440–456) Arteries, arterioles and capillaries Inflammation Arteritis (Aortitis) · Buerger's disease Arterial occlusive disease/ peripheral vascular disease Arteriosclerosis Atherosclerosis (Foam cell, Fatty streak, Atheroma, Intermittent claudication) · Monckeberg's arteriosclerosis · Arteriolosclerosis (Hyaline, Hyperplastic, oxycholesterol, cholesterol, LDL, trans fat) Stenosis Renal artery stenosis · Carotid artery stenosis Other Fibromuscular dysplasia · Degos disease · Aortoiliac occlusive disease · Raynaud's phenomenon/Raynaud's disease · Erythromelalgia Aneurysm/dissection/ pseudoaneurysm torso: Aortic aneurysm (Thoracic aortic aneurysm, Abdominal aortic aneurysm) · Aortic dissection · Coronary artery aneurysm head/neck: Cerebral aneurysm · Intracranial berry aneurysm · Carotid artery dissection · Vertebral artery dissection · Familial aortic dissection Vascular malformation Arteriovenous malformation · Arteriovenous fistula · Telangiectasia (Hereditary hemorrhagic telangiectasia) Vascular nevus Spider angioma · Halo nevus · Cherry hemangioma Veins Inflammation Phlebitis Venous thrombosis/ Thrombophlebitis primarily lower limb (Deep vein thrombosis) abdomen (Hepatic veno-occlusive disease, Budd–Chiari syndrome, May-Thurner syndrome, Portal vein thrombosis, Renal vein thrombosis) upper limb/torso (Paget-Schroetter disease, Mondor's disease) head (Cerebral venous sinus thrombosis) Post-thrombotic syndrome Varicose veins Varicocele · Gastric varices · Portacaval anastomosis (Hemorrhoid, Esophageal varices, Caput medusae) Other Superior vena cava syndrome · Inferior vena cava syndrome · Venous ulcer · Chronic venous insufficiency · Chronic cerebrospinal venous insufficiency Arteries or veins Vasculitis · Thrombosis · Embolism (Pulmonary embolism, Cholesterol embolism, Paradoxical embolism) · Angiopathy (Macroangiopathy, Microangiopathy) Blood pressure Hypertension Hypertensive heart disease · Hypertensive nephropathy · Essential hypertension  · Secondary hypertension (Renovascular hypertension) · Pulmonary hypertension · Malignant hypertension · Benign hypertension · Systolic hypertension · White coat hypertension Hypotension Orthostatic hypotension M: VAS anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot noco/syva/cong/lyvd/tumr, sysi/epon, injr proc, drug(C2s+n/3/4/5/7/8/9)