LDL Receptors

The discovery of the LDL receptor over 30 years ago has helped to elucidate the complex mechanisms underlying cholesterol homeostasis in the body. The LDL receptor is a protein whose primary function is to transport cholesterol into cells. Low-density lipoprotein (LDL) is a protein that carries cholesterol and is often referred to as the bad or lousy cholesterol. The LDL receptor removes both LDL particles and intermediate-density lipoproteins (IDL) particles from the blood through a process known as receptor-mediated endocytosis. The LDL receptor will interact with an LDL particle at the cell surface. This is a favorable location for this interaction because the pH is neutral in this area. Once the LDL particle binds to the receptor, an LDL particle-receptor complex is formed and then the complex is brought into the cell by endocytosis.

Once the LDL particle-receptor complex enters the cell it is released as an endosomes, an organelle within the cell. Within the endosome, there is a decrease in the pH (it is more acidic than the outside of the cell) and this change in acidity results in the receptor releasing the LDL particle from the LDL particle-receptor complex. The LDL particle will then be further broken down for the cell to use the cholesterol. There are two different fates for the LDL receptor after it releases the LDL particle. The receptor may either be destroyed or recycled back to the cell surface to be used again to bring in more LDL cholesterol. This process occurs primarily in the liver, the major organ for the removal of cholesterol from the body.

The levels of free cholesterol within the cell can regulate the synthesis of the LDL receptor. When there are low levels of cholesterol in the cell, there is an increase in the transcription of gene that makes the LDL receptor. One factor that regulates the LDL receptor is known as sterol-responsive element binding protein-2 (SREBP-2). Statins are a class of medications that are widely utilized to lower total and LDL cholesterol. One way in which they work is to increase the synthesis of the LDL receptor. This will allow for the removal of excess cholesterol from the body. Conversely, when cholesterol levels are high in the cell, the cell decreases the synthesis of the LDL receptor.

It has been discovered that some people may have inherited mutations for the gene that makes the LDL receptor. This would result in a condition known as familial hypercholesterolemia (FH) or high cholesterol. Patients who suffer from FH have elevated levels of LDL cholesterol, sometimes reaching nearly 700 mg/dl (normal values of LDL cholesterol should be < 130 mg/dl). Patients may be homozygous or heterozygous for the defect in the LDL receptor. Patients who are homozygous will have much greater LDL levels and often die in childhood. This mutation is less common than patients who are heterozygous. Patients who are heterozygous for the LDL receptor mutation are at an increased risk of developing heart disease in adulthood. These patients are the ones who typically receive cholesterol-lowering medication.

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