Low-density lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein which transport all fat molecules around the body in the extracellular water. These groups, from least dense, compared to surrounding water (largest particles) to most dense (smallest particles), are chylomicrons (aka ULDL by the overall density naming convention), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein and high-density lipoprotein (HDL). LDL delivers fat molecules to the cells and can drive the progression of atherosclerosis if they become oxidized within the walls of arteries.(Per 2004 United States Government Minimum Guidelines) Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein which transport all fat molecules around the body in the extracellular water. These groups, from least dense, compared to surrounding water (largest particles) to most dense (smallest particles), are chylomicrons (aka ULDL by the overall density naming convention), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein and high-density lipoprotein (HDL). LDL delivers fat molecules to the cells and can drive the progression of atherosclerosis if they become oxidized within the walls of arteries. It is important to note that LDL is not 'bad cholesterol'. It is an essential transport system for lipids the human body needs to survive, including cholesterol. There is both 'large' and 'small' particle LDL, and while only small is associated with cholesterol-related issues, neither is 'bad'. Even 'small' LDL is necessary to conduct nutrients to vessels that 'large' LDL cannot reach. 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/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/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 varying considerably. The conventional interpretation of cholesterol levels holds that higher levels of LDL particles pose increased risk of cardiovascular disease. LDL particles are thought to invade the endothelium and become oxidized, since the oxidized forms would be more easily retained by the proteoglycans. This view has been challenged as inaccurate and based on flawed research methodology. The issue remains controversial and vigorously contested in the literature. 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 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. LDL particles are formed as VLDL 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. 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. 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.