Cholesterol (in the form of LDL) is taken up into cells by receptor-mediated end

Question

Cholesterol (in the form of LDL) is taken up into cells by receptor-mediated endocytosis. Patients suffering from severe hypercholesterolemia have a defect in cholesterol uptake, which results in high levels of cholesterol in the blood. Researchers studying cells from a patient with this disease found that they are homozygous for mutations in the LDL receptor gene. When they tested the cells from the patient, they found that LDL is not able to bind to the surface of the patient’s cells at all, so LDL is not internalized.

a. In a healthy person, which membrane compartments/organelles does LDL travel through, starting from the extracellular space?

b. In a healthy person, which membrane compartments/organelles does the LDL receptor travel through, starting from the extracellular space?

c. Which cytoskeletal elements serve as “tracks” to move the LDL-containing vesicles to the correct organelles?

d. Which two components are required to work with that cytoskeletal element to move the LDL-containing vesicles within the cell?

e. Explain why the patient’s specific mutation causes such high levels of cholesterol to be in the blood?

Explanation / Answer

Cholesterol plays a critical role in the function of the cell membrane which has the highest concentration of cholesterol with around 25-30% of lipid in the cell membrane being cholesterol. Cholesterol has a role in membrane fluidity but it’s most important function is in reducing the permeability of the cell membrane.

Ans a: In a healthy person, Cholesterol in synthesized in the ER-Endoplasmic Reticulum and from there it gets transported to a variety of intracellular organelles. The cholesterol content of ER is very low, so most synthesized cholesterol is moved to other destinations. One destination is the plasma membrane where cholesterol is important for the structure and function of the cell membrane. And also cholesterol is also sent to other organelles, including mitochondria.

In healthy persons, cells express a set of proteins called lipid transfer proteins that ferry lipids and cholesterol between organelles. These proteins transport cholesterol from the different intracellular destinations bypassing the secretory pathway.

Lipid transfer proteins interact with membranes and bind specific lipids, in this case, LDL cholesterol. The proteins diffuse to target membrane, the mitochondrial membrane, and release into the membrane.

Ans b: The uptake of LDL into cells is an excellent example of receptor-mediated endocytosis. Cells express LDL receptor on their plasma membrane. The receptor binds to sites on Apoprotein in LDL. Bound receptors cluster in coated pits and are then endocytosed by clathrin. The endocytic vesicles acidify to become endosomes and the low pH causes a conformational change in the LDL receptor which releases LDL. The LDL receptor is sorted into vesicles that return the receptor to the cell membrane. The remaining endosome fuses with the lysosome where proteases and lipases can digest the lipoprotein. The component parts are then targeted to their appropriate subcellular location.

Ans c: Transport of LDL containing vesicles to the correct organelles is intresting. For those organelles that are part of the secretory pathway e.g. Golgi, lysosomes vesicular transport can deliver cholesterol.

Lipids and cholesterol were originally thought to diffuse through the plasma membrane of enterocytes but there is now evidence that protein channels facilitate the passage across the plasma membrane.

When a cell requires additional cholesterol, 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.

Ans d: The two components that are required to move the LDL-containing vesicles within the cell are:

1.PCSK9 or proprotein convertase subtilisin/kexin type 9

2. NPC1Niemann-Pick Like protein

PCSK9 or proprotein convertase subtilisin/kexin type 9 is an extracellular protein that binds the LDL receptor. In the endosome, PCSK9 binds tightly to the LDL receptor and prevents it from releasing LDL. Consequently, both LDL and receptor are delivered to the lysosome where they are degraded. The efect of PCSK9 is to reduce the number of LDL receptors on the cell membrane, decreasing a cell’s ability to take up LDL.

The channel responsible for allowing cholesterol to enter enterocytes has been identified, Niemann-Pick Like protein. It’s a protein with 13 transmembrane domains that localizes to the plasma membrane of enterocytes. Once LDL is delivered to the lysosome and lipases and proteases have processed LDL into individual molecules, the cholesterol needs to be moved from the lysosome to the ER. The Niemann-Pick proteins mediate exit of cholesterol from lysosomes. NPC1 is a transmembrane protein that resides in the membranes of lysosomes and late endosomes. NPC2 is soluble protein within the lysosome and endosome that binds cholesterol. The exact mechanism of how these proteins export cholesterol is unclear but one model is that NPC2 carries cholesterol to NPC1 and NPC1 mediates its transport across the membrane similar to NPC-like protein in enterocytes. Once out of the lysosome, cholesterol can be delivered to the ER or mitochondria by lipid-transport proteins.

Ans e:Mutations in Niemann-Pick proteins prevent the release of cholesterol from lysosomes, leading to the accumulation of cholesterol in lysosomes. The lysosomes become enlarged and begin to fill the cytoplasm of cells. Soon, the viability of cells is compromised. The liver and spleen are strongly affected by mutations in Niemann-Pick genes, but the main clinical manifestation in neurological as the activity of neurons is reduced as the cell fills with lysosomes

The LDLR gene provides instructions for making a protein called a low-density lipoprotein receptor. This type of receptor binds to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. By removing low-density lipoproteins from the bloodstream, these receptors play a critical role in regulating cholesterol levels. Some LDLR mutations reduce the number of low-density lipoprotein receptors produced within cells. Other mutations disrupt the receptors' ability to remove low-density lipoproteins from the bloodstream. As a result, people with mutations in the LDLR gene have very high levels of blood cholesterol. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and arteries that supply blood to the heart.

Less commonly, hypercholesterolemia can be caused by mutations in the APOB, LDLRAP1, or PCSK9 gene.

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