L22 Cholesterol

Question 1

Hyper-chylomicronemia can be caused by… (select all that apply)

A. apoA-I deficiency
B. ApoE deficiency
C. Lipoprotein lipase deficiency
D. ABCA1 mutations
E. ApoC-III mutations

Answer 1

C, E since they would result in NO chylomicron breakdown

B would result in increased chylomicron remnants since they will not be taken up by the liver

A, D concern HDL, not chylomicrons

Question 2

Abnormally high [LDL] in plasma can be caused by loss of function of… (select all that apply)

A. Lipoprotein lipase
B. LDL-R
C. ApoB-100
D. Pancreatic lipase
E. ABCA1

Answer 2

B, C since without either LDL-R or ApoB-100, LDL cannot be taken up by the liver or peripheral tissues

E is related to HCL not LDL
D is in the GIT so there’s no effect
A is related to chylomicrons

Question 3

Low HDL concentrations may result from mutations in… (select all that apply)

A. LDL-R
B. lipoprotein lipase
C. LCAT
D. ABCA1
E. apoA-I

Answer 3

C, D, E: LCAT is needed for HDL maturation (pre-HDL -> HDL), ABCA1 and apoA-I are needed for HDL precursor (pre-HDL)

Question 4

What does ABCA1 do?

Answer 4

It is a floppase that transport cholesterol from the inner leaflet to the outer leaflet so that it can interact with apoA-I (and pre-HDL)

Question 5

What does LCAT do?

Answer 5

It turns pre-HDL into HDL (maturation)

Question 6

What does CETP do?

Answer 6

It transports cholesterol ( cholesteryl ester) from HDL into VLDL and TAG from VLDL into HDL

Question 7

What happens if SRB1 is non-functional?

Answer 7

HDL cargo cannot be transferred to the liver

Question 8

What happens if you have LDLR-deficiency?

Answer 8

Too much LDL -> high CVD risk

Question 9

What happens if you have ABCA-1 deficiency?

Answer 9

Too little HDL -> high CVD risk

Question 10

What is good and bad cholesterol?

Answer 10

There is no good or bad cholesterol: too much LDL or too little HDL both cause high CVD risk

Question 11

HDL vs LDL: what do they do?

Answer 11

HDL removes excess cholesterol
LDL carries cholesterol to cells

Question 12

Where does NADPH come from?

Answer 12

PPP cycle

Question 13

TF: cholesterol synthesis requires NADH

Answer 13

F, it requires NADPH

Question 14

TF: cholesterol can be synthesized by isoprenoids

Answer 14

True

Question 15

What is the key regulatory enzyme in cholesterol synthesis and what does it produce?

Answer 15

HMG-CoA reductase, mevalonate

Question 16

TF: cholesterol can be synthesized from acetyl-CoA

Answer 16

True

Question 17

How much ATP and NADPH is required for the synthesis of 1 cholesterol molecule in the mevalonate pathway

Answer 17

36 ATP and 16 NADPH

Question 18

What is farnesyl pyrophosphate?

Answer 18

It is a cholesterol precursor (right before squalene) that acts as a lipid anchor meaning it anchors the protein to the membrane (non-raft)

Question 19

What are the 2 ways cholesterol is regulated through homeostasis?

Answer 19

Body: diet + synthesis vs excretion
Cell: uptake from circulation vs efflux from cell

Question 20

LDLR vs ABCA1: which one is involved in uptake of cholesterol and which one is involved in efflux of cholesterol?

Answer 20

LDLR = uptake: cholesterol from LDL is absorbed into cell

ABCA1 = efflux: cholesterol is transformed into preHDL (then to HDL)

Question 21

What is cholesterol excreted as?

Answer 21

Build acids and biliary cholesterol

Question 22

What are the 2 ways to regulate cholesterol synthesis via HMG-CoA reductase?

Answer 22

1. Energy state
2. Gene regulation ‘ sensing [cholesterol]

Question 23

What is the melavonate pathway

Answer 23

It is the pathway for cholesterol and other isoprenoid synthesis (aka HMG-CoA reductase pathway or isoprenoid pathway)

Question 24

In what state is HMG-CoA reductase in when high [AMG]/[ATP]

Answer 24

High [amg/atp] describes a low energy state. The lack of atp means cholesterol synthesis cannot occur so hmg-coa reductase is off/inactive and phosphorylated

Question 25

What does AMPK do?

Answer 25

It phosphorylates hmg-coa reductase to turn it off

Question 26

How is cholesterol synthesis regulated through gene regulation?

Answer 26

High intracellular cholesterol makes it so that insig stays bound to Scap thus inhibiting Scap-SREBP transport to golgi

Low intracellular cholesterol allows Scap-SREBP transport to golgi, where the SREBP (transcription factor) is cleaved by S1P and S2P. Then, SREBP can activate SRE (sterol-response element) found in promoter to increase hmg-coa reductase and LDL-R synthesis increasing cholesterol synthesis and LDL uptake respectively (increasing cholesterol uptake)

Question 27

How can cholesterol synthesis be pharmacologically regulated?

A. Hmg-coa synthase inhibitor
B. Hmg-coa synthase activator
C. Hmg-coa reductase inhibitor
D. Hmg-coa reductase activator

Answer 27

C, hmg-coa reductase inhibitor (aka statins)

Question 28

What would high levels of SREBP in the nucleus indicate about cholesterol levels?

Answer 28

It would indicate low cholesterol levels

Question 29

What is the function of cholesteryl esters?

1. Intestine, liver, adipocyte
2. Inside cells
3. Plasma

Answer 29

1. Chylomicrons (intestine), VLDL (liver), lipid vesicles (Adipocyte)
   - GPAT
2. Lipid droplets, VLDL (inside cells)
   - ACAT transfers the cholesterol into the cells by turning it into cholesteryl ester
3. HDL (plasma)
   - LCAT

Question 30

What are the 4 sterol derivatives

Answer 30

Cholesteryl ester
Bile salts
Hormones
Vitamin D

Question 31

What is the function of VLDL

Answer 31

Delivering TG to adipocytes and become LDL

Question 32

What is the function of LDL

Answer 32

Supply various organs with cholesteryl ester

Question 33

To what organs does HDL deliver cholesterol to and what happens to the cholesterol?

Answer 33

Liver -> bile acids
Adrenal glands -> steroid hormones
Skin -> vitamin D

Question 34

Which organ is the central hub for cholesterol metabolism and why?

Answer 34

Liver, it produces cholesterol for other organs via LDL

Question 35

How is hmg-coa reductase regulated (by which substrates)

Answer 35

AMP/ATP ratio and [cholesterol]

Question 36

What does statin do

Answer 36

It inhibits hmg-coa reductase and deceases [LDL]