Cholesterol 3

Question 1

Where would you expect MTP to be the most abundant?

Answer 1

In the ER LUMEN of:

• Hepatocytes
• Enterocytes

**Thats where lipoproteins need to be made

Question 2

What enzyme mediates the first step in lipoprotein assemby?

- What does it do?

Answer 2

• MTP transfers lipid from ER membrane to a newly translated apoB

**Can then add more later to give particle more lipids

Question 3

What subunits make up MTP?

- what do they do?

Answer 3

-MTP is a HETEROdimer

Subnunits:
- Large Subunit - facilates the actual Transfer activity

• Protein Disulfid Isomerase (PDI) - this maintains large subunit in a soluble form (may also transfer MTP to ER)

Question 4

What Apo proteins would you expect to be on a nascent chylomicron?

Answer 4

• ApoB-48

- Apo A-4

Question 5

What gives nascent chylomicrons Apo CII and Apo E and why is this necessary?

Answer 5

• HDL gives some of its apo protiens up
• Apo CII - necessary to bind to LPL
• Apo E - necessary to bind to LPR receptor

Question 6

Does LDL have apo E on it?

- why or why not?

Answer 6

NO

- VLDL and IDL both have Apo E but they don’t really need it because ApoB100 has a LDL binding domain

Question 7

What are ABCG1 and ABCA1 important for and where are they expressed?

Answer 7

• They extrude free cholesterol from tissue to pre-HDL to make it HDL

ABCA1 - located on Hepatocytes and peripheral tissue

ABCG1 - located on periferal tissue

Question 8

What acts to mature an HDL particle?

Answer 8

LCAT - esterfies cholesterol to puff up the particle

Question 9

Why is the interaction between ABCG1, ABCA1, and HDL so important?

Answer 9

• If pulls cholesterol out of the periphery and puts it back in the liver where it can be make into to bile salts etc.

**Pulling fat out of macrophages = REALLY important Job

Question 10

What apo protein is needed to get HDLs back to the liver?

Answer 10

Apo-A1, binds to SRB1

Question 11

T or F: there is a direct correlation between PLASMA cholesterol and coronary death in men.

Answer 11

True

Question 12

Why is it important to be in a fasting state do do a lipid profile?

Answer 12

1. Cholesterol doesn’t change much with fasting so its not for that reason
2. Reason: Chylomicrons will being carrying around TAGs in the fed state and you would end up measuring TAGs for those too

Question 13

What is the the Friedwald Formula?

Answer 13

LDL (mg/dL) = Total Cholesterol - HDL - (Triglyceride/5)

Question 14

What level of total cholesterol is associated with inherited disorders?

Answer 14

> 302 mg/dL

Question 15

What level of cholesterol puts you at for coronary heart disease?

Answer 15

> 251 mg/dL

Question 16

What level of TAGs puts you at risk for pancreatitis?

Answer 16

> 886 mg/dL

Question 17

What level of HDL is associated with being protective agianst coronary heart disease?

Answer 17

> 54 mg/dL

Question 18

Monogenic Dyslipidemia

• % of referrals
• Screen family?
• Lifestyle changes
• Drugs?

Answer 18

**Involves a single messed up gene

• 5-10% of referrals
• SCREENING OF FAMILY MEMBERS IS ESSENTIAL
• Lifestyle changes may have little impact
• MOST REQUIRE DRUG THERAPY

Question 19

Polygenic Dysipidemia

• genes
• Lifestyle changes

Answer 19

** Multiple genes each contribute a small amount to the overall phenotype

**This makes up the majority of patients

• Most will respond well to Lifestyle changes in diet and exercise

Question 20

What is familial hypercholesterolemia?

• mode of inheritance
• defect
• plasma lipids

Answer 20

• Autosomal Dominant (1/500)
• DEFECT in LDL Receptor
• Hypercholesteremia (chol.) or mixed hyperlipidemia (chol. and tags)

why?
- Because you are pulling any LDL out of your blood

Question 21

What is familial combined hyperlipidemia?

• mode of inheritance
• defect
• plasma lipids

Answer 21

• Autosomal Dominant (1/50)
• OVERproduction of apoB100
• Hypercholesterolemia (chol.) or mixed hyperlipidemia (chol. and tags)

why?
- Because you are pushing out too many too many VLDL

Question 22

What is familial dysbetalipoproteinemia (type III hyperlipidemia)?

• mode of inheritance
• defect
• plasma lipids

Answer 22

• Autosomal Recessive (1/5000)
• Presence of E2/E2 isoform
• Mixed Hyperlipidemia (III) (chol. and tags)

why?
- Because E2/E2 isoform leads to defective remnant binding to LDL receptor

Question 23

What does a mutation in the cytoplasmic domain of the LDL receptor do?

Answer 23

• Decreased Internalization (receptor wont get taken in after binding)

Question 24

What does a mutation in the membrane spanning domain of the LDL receptor cause?

Answer 24

Secretion of the Receptor (it won’t be held in membrane)

Question 25

What does a mutation in the O-linked sugars domain of LDL receptor do?

Answer 25

Nothing

Question 26

What does a mutation in the EGF region of the LDL receptor do?

Answer 26

Decreased:

• Recycling
• Transport to membrane

Question 27

What does a mutation in the Ligand binding domain of the LDL receptor cause?

Answer 27

Decreased:

• Binding
• Transport to membrane

Question 28

What does a mutation in the signal sequence of the LDL recptor cause?

Answer 28

Decreased mRNA

Question 29

What does SCAP do?

Answer 29

SCAP senses the amount of oxycholestrol in the cell and if its low it activates SPEBP to make more LDL receptors

Question 30

What is the difference in a stable and unstable Atherosclerotic Plaque?

Answer 30

Stable:

• Thick Fibrous Cap
• Unlikely to cause an acute event

Unstable:
- Thin fibrous Cap - can rupture and cause an acute event

Question 31

What is the desirable level for total cholesterol?

Question 32

What is the desirable level for TAGs?

Question 33

What level of HDL is associated with increased risk of coronary heart disease?