Cholesterol

Question 0

How do cells get cholesterol?

Answer 0

in cell synthesis and diet

Question 1

What are the roles of cholesterol in the body?

Answer 1

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)

Question 2

What are the important step for cholesterol synthesis?

Answer 2

Acetyl co A – > cholesterol

Rate limiting step is acetyl co A via HMG co A reductase to mevalonic acid

Question 3

How does cholesterol get to the mitchondria?

Answer 3

Can’t get to mitchondria via secretory vesicles bc not in secretory pathways, need lipid transfer proteins (LTPs)

Question 4

What is the structure of HMG reductase?

Answer 4

7 trans membrane protein with a catalytic domain pointed to the cytosol

Question 5

How do statins inhibit HMG co A reductase?

Answer 5

bind competitively to catalytic domain

Question 6

What happens when cholesterol levels get high in a normal body?

Answer 6

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

Question 7

What happens to a normal body when cholesterol level is low?

Answer 7

transcription factors increase the synthesis of HMG co Reductase (which makes cholesterol) and LDL receptors which increase the amount cholesterol in the cell

Question 8

What is the transcription factor associated with increasing cholesterol levels?

Answer 8

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

Question 9

How does cholesterol move in the cell and body?

Answer 9

attached to carriers, like LDL

Question 10

What are the different type of cholesterol carriers?

Answer 10

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

Question 11

What determines the density of lipoproteins?

Answer 11

Amt of cholesterol to protein, protein is dense so the more protein (the less cholesterol) the less dense

Question 12

How does cholesterol get into body?

Answer 12

Niemann Pick like Proteins are transmembrane receptor that moves in cholesterol from the lumen of the intestine into body

Question 13

What is the drug that blocks Niemann Pick like receptors?

Answer 13

ezentomide; can’t transport cholesterol from the lumen of the intestines into the cytosol so have a decrease in serum cholesterol

Question 14

How do LDL receptors bind LDL?

Answer 14

Bind Apo B protein on LDL

Question 15

How do cholesterol and lipids etc get bound in cells?

Answer 15

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

Question 16

What happens to LDL once it binds to a receptor?

Answer 16

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)

Question 17

How is the recycling of LDL receptors inhibited?

Answer 17

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

Question 18

What is the problem with targeting cholesterol synthesis through the HMG co A reductase pathways?

Answer 18

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

Question 19

Once the lysosome degrades the cholesterol, how does it get out of the lysosome?

Answer 19

Niemann pick proteins
NP1 is a transmembrane receptor
NP2 acts like a chaperone and brings cholesterol to the memrbane

Question 20

What is the effect of mutations in Neimann Pick proteins?

Answer 20

lysosomes can’t get rid of cholesterol which cause cell death eventually

Question 21

What are the longer term effects of high cholesterol?

Answer 21

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

Question 22

What is mutated in famillial hypercholesterolemia?

Answer 22

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)

Question 23

What is a surgical treament option for famillial hypercholesterimia and why is it successful?

Answer 23

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

Question 24

What are common phenotypes of famillial hypercholesterimia ?

Answer 24

lipid deposits around eyes
xanthomas (macrophage build ups that are lesions around the tendons)
deposits of cholesterol on aterial walls leading to atherosclerosis
myocardial ischemia, stroke, heart attack
high serum cholesterol (greater than 200 abnormal)
less than 10% LDL receptor function
low rate of catabolism of LDL

Question 25

What are treatment option for famillial hypercholesteremia?

Answer 25

1) Resins that block reuptake of bile by liver (push all cholesterol out)
2) HMG co A reductase inhibitor (statin)
3) Portocaval shunt (not good decrease, high levels ammonia)
4) illeal exclusion (can’t reabsorb bile)
5) LDL aphoresis (short term, lifelong care)
6) APO B antisense (block uptake of LDL, but means build up of LDL in liver)
7) Anti PCSKA - not bad, keeps function receptors active
8) Liver transplant
9) gene therapy - not get good

Question 26

How are bile acid resins supposed to work?

Answer 26

decreased reabsorption of bile, increased metabolism of cholesterol into bile acid –> more LDL-R because need more cholesterol in cell –> increased removal of LDL from blood— > reduced LDL in plasma

Question 27

Why don’t resins work in patients with familial hypercholesteremia?

Answer 27

mechanism for lowering blood cholesterol is the increased expression of LDL-receptors, but patients with homozygous FH can’t express LDL-R so doesn’t work