low-density lipoprotein low-density lipoprotein low-density lipoprotein (ldl) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. these groups, from least dense to most dense, are chylomicrons (aka uldl by the overall density naming convention), very low-density lipoprotein (vldl), intermediate-density lipoprotein (idl), low-density lipoprotein (ldl) and high-density lipoprotein (hdl). ldl delivers fat molecules to cells. ldl is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries. ldl has been associated with the progression of atherosclerosis and blockage of the artery lumen, because it can carry cholesterol into smaller vessels. but ldl is also essential for carrying lipids that keep the human body alive, including in those small vessels. overview lipoproteins transfer lipids (fats) around the body in the extracellular fluid, making fats available to body cells for receptor-mediated endocytosis. lipoproteins are complex particles composed of multiple proteins, typically 80–100 proteins per particle (organized by a single apolipoprotein b for ldl and the larger particles). a single ldl particle is about 220–275 angstroms in diameter, typically transporting 3,000 to 6,000 fat molecules per particle, and varying in size according to the number and mix of fat molecules contained within. the lipids carried include all fat molecules with cholesterol, phospholipids, and triglycerides dominant; amounts of each vary considerably. the common clinical interpretation of blood lipid levels is that high ldl is associated with increased risk of cardiovascular diseases. biochemistry structure each native ldl particle enables emulsification, i.e. surrounding the 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) of esterified and unesterified 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.) to 27.5 nm 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. 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 cryogenic electron microscopy, has been recently described. physiology ldl particles are formed when triglycerides are removed from vldl by the lipoprotein lipase enzyme (lpl) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters. transport into the cell when a cell requires additional cholesterol (beyond its current internal hmgcoa production pathway), it synthesizes the necessary ldl receptors as well as pcsk9, a proprotein convertase that marks the ldl receptor for degradation. ldl receptors are inserted into the plasma membrane and diffuse freely until they associate with clathrin-coated pits. when ldl receptors bind ldl particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell. vesicles containing ldl receptors bound to ldl are delivered to the endosome. in the presence of low ph, such as that found in the endosome, ldl receptors undergo a conformation change, releasing ldl. ldl is then shipped to the lysosome, where cholesterol esters in the ldl are hydrolysed. ldl receptors are typically returned to the plasma membrane, where they repeat this cycle. if ldl receptors bind to pcsk9, however, transport of ldl receptors is redirected to the lysosome, where they are degraded. role in the innate immune system ldl 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. ldl size patterns ldl can be grouped based on its size: large low density ldl particles are described as pattern a, and small high density ldl particles are pattern b. pattern b has been associated by some with a higher risk for coronary heart disease.: 1–10 this is thought to be because the smaller particles are more easily able to penetrate the endothelium of arterial walls. 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. other studies have shown no such correlation at all. some evidence suggests the correlation between pattern b and coronary heart disease 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. 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 ("buoyant") ldl. with continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including nmr spectroscopy, research studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured particle concentrations. oxidized ldl oxidized ldl is a general term for ldl particles with oxidatively modified structural components. as a result, from free radical attack, both lipid and protein parts of ldl can be oxidized in the vascular wall. besides the oxidative reactions taking place in vascular wall, oxidized lipids in ldl can also be derived from oxidized dietary lipids. oxidized ldl is known to associate with the development of atherosclerosis, and it is therefore widely studied as a potential risk factor of cardiovascular diseases. atherogenicity of oxidized ldl has been explained by lack of recognition of oxidation-modified ldl structures by the ldl receptors, preventing the normal metabolism of ldl particles and leading eventually to development of atherosclerotic plaques. of the lipid material contained in ldl, various lipid oxidation products are known as the ultimate atherogenic species. acting as a transporter of these injurious molecules is another mechanism by which ldl can increase the risk of atherosclerosis. testing blood tests commonly report ldl-c: the amount of cholesterol which is estimated to be contained with ldl particles, on average, using a formula, the friedewald equation. in clinical context, mathematically calculated estimates of ldl-c are commonly used as an estimate of how much low density lipoproteins are driving progression of atherosclerosis. the problem with this approach is that ldl-c values are commonly discordant with both direct measurements of ldl particles and actual rates of atherosclerosis progression. 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. 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. it only estimates them using the friedewald equation by subtracting the amount of cholesterol associated with other particles, such as hdl and vldl, assuming a prolonged fasting state, etc.: l ≈ c − h − k t 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. if both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dl, may be used l = c − h − 0.16 t this formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual ldl particle concentration because the percentage of fat molecules within the ldl particles which are cholesterol varies, as much as 8:1 variation. there are several formulas published addressing the inaccuracy in ldl-c estimation. the inaccuracy is based on the assumption that vldl-c (very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. a new formulae published recently addresses this issue by using an adjustable factor or by using a regression equation. there are few studies which have compared the ldl-c values derived form this recently published formula and values obtained by direct enzymatic method. direct enzymatic method are found to be accurate and it has to be the test of choice in clinical situations. in the resource poor settings, the option of using the formula has to be considered. however, the concentration of ldl particles, and to a lesser extent their size, has a stronger and consistent 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. 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. normal ranges in the us, 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: 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; 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 (higher than tim russert's value shortly prior to his heart attack) 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.