Cholesterol 3 Flashcards
How are LDL particles digested in the cell?
Attaches to the LDL receptor leading to endocytosis taking up the particle
This then progresses to reach the lysosome, lysosomal proteases will then hydrolyse apolipoproteins while cholesterol esterases hydrolyze the core cholesterol esters to cholesterol is it is available for membrane synthesis
LDR is recycled, the intracellular cholesterol intake results in an increase in Acyl-CoA acyl transferase synthesis and a decrease in HMG CoA Reductase and LDL receptor synthesis
What is familial cholesterolemia?
When there is high cholesterol due to a defect in the LDL receptor caused by one of three mutations, this results in an inability to shut down cholesterol synthesis
What are the features of familial cholesterolemia?
There is high plasma cholesterol
Homozygous individuals are very rare with serum levels of roughly 5 times normal
There is an increased risk of a heart attack with many dying before 20
How is cholesterol taken up by cells?
LDL binds to the LDL receptor, this results in internalization via recruitment of adapter proteins and a clatherin coat with dynamin pinching off the vesicle
What were the features of the familial cholesterolemia phenotype as discovered by brown and Goldstein?
Fibroblasts in FH cells synthesized cholesterol at an abnormally high rate
Normal cells would reduce HMG-coA reductase activity in response to LDL, while in FH cells LDL did not change the HMG-coA recutase activity
These facts would suggest that LDL is taken up into cells to regulate HMG-coA reductase and hence cholesterol synthesis
What is the cause of familial cholesterolemia?
A mutation in the LDL receptor preventing LDL from being taken up by the cell and regulating HMG-coA reductase
What are the different types of mutants in the LDL receptor?
Mutants that are unable to fold and be targeted to the membrane
Mutants that are unable to bind LDL
Mutants that are unable to be endocytosed
What did one of the mutations for Familial cholesterol lead to?
One class was missing a cytosolic domain, where either the domain was completely missing or there was a tyrosine to a cysteine mutation leading to identification of the Asn-Pro-X-Tyr sorting signal which is an endocytosis motif that interacts with AP2 proteins
What happens to the cholesterol in LDL when LDL is taken up by the cell?
Is used to build up cholesterol ester droplet
Reduces the activity of HMG- coA reductase
Travel the cell membrane
Increase the activity of Acyl-CoA Transferase
Decrease the synthesis of LDL receptors
