Cholesterol Flashcards
How do cells get cholesterol?
in cell synthesis and diet
What are the roles of cholesterol in the body?
1) Important for regulating the cell membrane (more cholesterol, less permeable)
2) Precursors for other metabolic molecules (bile synthesis in liver, synthesis of all steroids)
What are the important step for cholesterol synthesis?
Acetyl co A – > cholesterol
Rate limiting step is acetyl co A via HMG co A reductase to mevalonic acid
How does cholesterol get to the mitchondria?
Can’t get to mitchondria via secretory vesicles bc not in secretory pathways, need lipid transfer proteins (LTPs)
What is the structure of HMG reductase?
7 trans membrane protein with a catalytic domain pointed to the cytosol
How do statins inhibit HMG co A reductase?
bind competitively to catalytic domain
What happens when cholesterol levels get high in a normal body?
HMG co A reductase is targeted for degradation
HMG co A is bound to INSIG which is a transmembrane protein bound to a ubiquitin ligase and a ATP ase, the ubligase ubiquitinates the domain and the ATMP ase removes the enzyme from the membrane, the receptor/enzyme is then degraded by a proteosome
What happens to a normal body when cholesterol level is low?
transcription factors increase the synthesis of HMG co Reductase (which makes cholesterol) and LDL receptors which increase the amount cholesterol in the cell
What is the transcription factor associated with increasing cholesterol levels?
Sterol response element (SRE)
The SRE sits in the membrane and binds to Scap when cholesterol is high, that holds the protein in the ER membrane so it can’t act like a TF
Low levels of cholesterol, SRE leaves teh ER and goes to the golgi, still attached to Scap and then is cleaved by proteases in the golgi so the SRE can go to the nucleus and activate transcription
How does cholesterol move in the cell and body?
attached to carriers, like LDL
What are the different type of cholesterol carriers?
Chylomicrons : largest, first transporter, can’t get directly into capillaries from intestines so go through the lymph system and systemic circulation depositing before liver
IDL - intermediate density lipoproteins (to liver)
VLDL- out of liver, deposit fatty acids
LDL- goes back to liver or tissue
HDL- after tissues if there is too much cholesterol it is repackaged as HDL and sent back to the liver
What determines the density of lipoproteins?
Amt of cholesterol to protein, protein is dense so the more protein (the less cholesterol) the less dense
How does cholesterol get into body?
Niemann Pick like Proteins are transmembrane receptor that moves in cholesterol from the lumen of the intestine into body
What is the drug that blocks Niemann Pick like receptors?
ezentomide; can’t transport cholesterol from the lumen of the intestines into the cytosol so have a decrease in serum cholesterol
How do LDL receptors bind LDL?
Bind Apo B protein on LDL
How do cholesterol and lipids etc get bound in cells?
Bile salts and enzymes break down large macromolecules or fats into smaller units, enterocytes (epi cells in intestine) transport in cholesterol and trigylcerides via Niemann Pick like proteins, and then cells package them in ER and Golgi into chylomicrons
What happens to LDL once it binds to a receptor?
ApoB on LDL binds to a transmembrane receptor; endocytosis occurs, the endocytosed vesicle has a lower pH so the molecules and the receptor disengage, molecules from LDL then go to a lysosome to be broken down into components and receptor gets recycled back to membrane (usually)
How is the recycling of LDL receptors inhibited?
PCSK 9 binds to the receptor and LDL and doesn’t let them seperate in the endocytotic vesicle so the receptor is also degraded, when there is an increase in receptors, there is generally also an increase in PCSK 9 expression
What is the problem with targeting cholesterol synthesis through the HMG co A reductase pathways?
When the amount of cholesterol in the cell decreases, the cell wants to express more LDL receptors to bring in more cholesterol, this is good because it lowers serum cholesterol, unfortunately, this also triggers cells to express PCSK 9 which degrades receptors so the effect is muted
Once the lysosome degrades the cholesterol, how does it get out of the lysosome?
Niemann pick proteins
NP1 is a transmembrane receptor
NP2 acts like a chaperone and brings cholesterol to the memrbane
What is the effect of mutations in Neimann Pick proteins?
lysosomes can’t get rid of cholesterol which cause cell death eventually
What are the longer term effects of high cholesterol?
When LDL has been in the blood for awhile, it undergoes changes like oxidation, this allows it to be identified by macrophages via a savenger receptor (one that recognizes general patterns, not specific); these macrophages take up a lot of LDL and become FOAM cells that attract an immune response, lyse, and deposit cholesterol crystals on arteries leading to atherloscrosis
What is mutated in famillial hypercholesterolemia?
generally a mutation in the LDL receptor so can’t take up LDL from blood and get very high LDL levels in young children (when homozygous)
What is a surgical treament option for famillial hypercholesterimia and why is it successful?
Liver transplant (full cadaveric, auxiliary cadavaric - leave in old one, and live), because 75% of LDL is taken up in the liver so getting normal LDL receptor function in the liver “cures” the phenotype
