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. 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 22–27.5 nanometers 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. Elevated LDL is an established causal factor for the development of atherosclerotic cardiovascular disease. A normal non-atherogenic LDL-C level is 20–40 mg/dl. Guidelines recommend maintaining LDL-C under 2.6 mmol/L (100 mg/dl) and under 1.8 mmol/L (70 mg/dL) for those at high risk.
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 difficult for biochemists because of its heterogeneous structure. However, the structure of LDL at human body temperature in native condition, with a resolution of about 16 Angstroms using cryogenic electron microscopy, has been described in 2011.
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 the same protein transport shell), containing a higher proportion of cholesterol esters.
Transport into the cell When a cell requires more cholesterol than its HMG-CoA pathway can produce, 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 endosomes. 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 lysosomes, 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.
Innate immune system LDL interferes 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.
Size patterns LDL can be grouped based on its size: large low-density LDL particles are described as pattern A, and small high-density ("small dense") LDL particles are pattern B. Pattern B has been associated by some with a higher risk for coronary artery disease. This is thought to be because the smaller particles are more easily able to penetrate the endothelium of arterial walls. Pattern I, or 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. Some evidence suggests the correlation between pattern B and coronary artery 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 standard 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 shown a stronger correlation between clinically evident human cardiovascular events and quantitatively measured particle concentrations.
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