Cholesterol and Lipoproteins

Question 1

3 lipids that make up membranes

Answer 1

Phospholipids 75%
Cholesterol 20%
Glycolipids 5%

Question 2

Order the lipoproteins from most dense to least dense

Answer 2

HDL > LDL > IDL > VLDL > Chylomicron

Question 3

Where does cholesterol synthesis take place

Answer 3

Cytoplasm and ER

Question 4

Molecular mechanism of cholesterol synthesis upregulation

Answer 4

SREBP-SCAP moves from ER to Golgi. SREBP is cleaved, and DNA-binding domain binds SRE in nucleus to enhanc transcription

Question 5

How is cholesterol synthesis down regulated

Answer 5

Insig binds SCAP, keeping it in the ER

Question 6

Effect of Insulin on HMG-CoA Reductase expression

Answer 6

Up-regulation of HMG-CoA (lots of available Acetyl-CoA in the fed state)

Question 7

Effect of Glucagon on HMC-CoA Reductase expression

Answer 7

Down-regulation of HMG-CoA

Question 8

Effect of AMPK on HMG-CoA Reductase

Answer 8

AMPK phosphorylates the reductase, inactivating it

Question 9

Effect of PPP on HMG-CoA Reductase

Answer 9

PPP (Phosphoprotein Phosphatase) dephosphorylates the protein, activating it

Question 10

What do statins do

Answer 10

Inhibit HMG-CoA Reductase

Question 11

What do bile salts do

Answer 11

Solubilize dietary lipids, exposing them to digestive enzymes and making it easier for them to be absorbed in the intestine by corralling them into micelles

Question 12

Lipoprotein structure

Answer 12

Shell: Phospholipids, Free cholesterol, Apolipoproteins
Core: Cholesterol esters and TAG’s
Diameter = 50-12000 Å

Question 13

Absorption of TAG into body

Answer 13

Combine with bile salts, pancreatic lipase, and colipase to create 2MAG and free FA’s

Question 14

VLDL vs Chylomicrons; which is endogenous, and which is exogenous

Answer 14

Chlyomicrons are exogenous (deliver dietary TAG to cells) and VLDL are endogenous (deliver non-dietary TAG to cells)

Question 15

Difference between the two liver isozymes for HMG-CoA Synthase

Answer 15

One in mitochondria is for ketone body formation, one in cytosol is for cholesterol synthesis

Question 16

Cholesterol synthesis up to Mevalonate

Answer 16

Acetyl-CoA x2 -> Acetoacetyl-CoA -> HMG-CoA -> Mevalonate

Thiolase (Condensation)
HMG-CoA Synthase
HMG-CoA Reductase

Question 17

What co-reactants does HMG-CoA Reductase use?

Answer 17

CO2 + NADPH > NADP + CoA

Removal of CoA makes step irreversible

Question 18

Carbon amounts from Mevalonate to cholesterol

Answer 18

Mevalonate 6
5C
10C
15C
Squalene 30C
Cholesterol 27C

Question 19

ACAT vs LCAT

Answer 19

ACAT esterifies Cholesterol in the ER by adding a FA to allow for storage and transportation
makes it more hydrophobic

LCAT does the same thing, but in the plasma

Question 20

Structure of the intestinal micelle

Answer 20

Surrounded by bile salts, with a core of cholesterol phospholipids and TAG

Question 21

Chylomicron absorption mechanism

Answer 21

1) Produced by intestinal mucosal cells with Apo-B48
2) Bumps into HDL, gets App C-II and E
3) ApoCII activates LPL, which removes TAG (free FA to tissues, glycerol to liver)
4) HDL picks up ApoCII
5a) If E, remnant binds to receptor (via ApoE) on Liver and is recycled by lysosome
5b) If no E, remnant becomes a nascent HDL shell

Question 22

Glycine/Taurine ratio and importance

Answer 22

3:1, and allows them to be more amphipathic and as a result, be better detergents

Question 23

VLDL absorption mechanism

Answer 23

1) Produced from liver with Apo-B100
2) Bumps into HDL, gets App C-II and E
3) ApoCII activates LPL, which removes TAG (free FA to tissues, glycerol to liver)
4) HDL picks up ApoCII, VLDL then becomes LDL
5) LDL then delivers cholesterol to peripheral tissues via LDLR

Question 24

LDLR mechanism

Answer 24

1) LDL binds to clathrin-coated pits
2) LDLR internalized, degraded by lysosome
2) degradation of TAG and CE
4) receptor recycled back to surface

Question 25

Effects of LDLR ingestion

Answer 25

Leads to more free cholesterol leaving the lysosome

3 effects
1) Suppresses HMG-CoA Reductase
2) Activates ACAT
3) Decreases LDL on the cell surface

Question 26

HDL absorption mechanism

Answer 26

1) produced from nascent Chylomicron discs
2) ApoA1 activates LCAT to esterify cholesterol picked up from ABCA1 and ABCG1
3) Esters are then added to the middle of the disc
4) SRB1 (scavenger receptor) removes HDL from the discs and brings it into the liver
4b) CE can also be removed by CETP and transferred to VLDL

Question 27

CETP (Cholesterol Ester Transfer Protein)

Answer 27

TG to HDL and CE to VLDL

Question 28

How does Atherosclerosis occur?

Answer 28

1) injury to tunica intima
2) LDL flows in, and are oxidized by ROS
3) Monocytes proliferate, become macrophages, engulf LDL’s and become foamy cells
4) Foamy cells stimulate smooth muscle to form plaque
5) Rupture of plaque leads to thrombus and occlusion of the lumen

Question 29

How does HDL prevent Atherosclerosis

Answer 29

1) HDL picks up esters from macrophages via ABCA1 and ABCG1
2) Inhibit oxidation of LDL
3) Produces NO to repair endothelium and prevent inflammation

Question 30

How does Cholestyramine work?

Answer 30

It sequesters cholesterol, causing up regulation of LDLR to produce more bile salts, reducing plasma cholesterol

Improves statin performance

Question 31

How does a PCSK9 inhibitor help lower cholesterol?

Answer 31

When a statin is added, it amplifies the # of LDLR, which also increases the amount of PCSK9

Inhibiting PCSK9 allows there to be more LDLR on the surface of the cell

Question 32

How do B100 inhibitors work

Answer 32

Inhibit B100, preventing circulating VLDL, which means less LDL and cholesterol in the blood

Discontinued because of an accumulation of TAG in the liver

Question 33

How does Bempedoic acid work

Answer 33

Inhibits ATP Citrate Lyase

Some statins can cause myotoxicity in patients, BA inhibits cholesterol production in the liver, but not the muscle