Cholesterol 3 Flashcards
Where would you expect MTP to be the most abundant?
In the ER LUMEN of:
- Hepatocytes
- Enterocytes
**Thats where lipoproteins need to be made
What enzyme mediates the first step in lipoprotein assemby?
- What does it do?
- MTP transfers lipid from ER membrane to a newly translated apoB
**Can then add more later to give particle more lipids
What subunits make up MTP?
- what do they do?
-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)
What Apo proteins would you expect to be on a nascent chylomicron?
- ApoB-48
- Apo A-4
What gives nascent chylomicrons Apo CII and Apo E and why is this necessary?
- HDL gives some of its apo protiens up
- Apo CII - necessary to bind to LPL
- Apo E - necessary to bind to LPR receptor
Does LDL have apo E on it?
- why or why not?
NO
- VLDL and IDL both have Apo E but they don’t really need it because ApoB100 has a LDL binding domain
What are ABCG1 and ABCA1 important for and where are they expressed?
- 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
What acts to mature an HDL particle?
LCAT - esterfies cholesterol to puff up the particle
Why is the interaction between ABCG1, ABCA1, and HDL so important?
- 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
What apo protein is needed to get HDLs back to the liver?
Apo-A1, binds to SRB1
T or F: there is a direct correlation between PLASMA cholesterol and coronary death in men.
True
Why is it important to be in a fasting state do do a lipid profile?
- Cholesterol doesn’t change much with fasting so its not for that reason
- Reason: Chylomicrons will being carrying around TAGs in the fed state and you would end up measuring TAGs for those too
What is the the Friedwald Formula?
LDL (mg/dL) = Total Cholesterol - HDL - (Triglyceride/5)
What level of total cholesterol is associated with inherited disorders?
> 302 mg/dL
What level of cholesterol puts you at for coronary heart disease?
> 251 mg/dL
What level of TAGs puts you at risk for pancreatitis?
> 886 mg/dL
What level of HDL is associated with being protective agianst coronary heart disease?
> 54 mg/dL
Monogenic Dyslipidemia
- % of referrals
- Screen family?
- Lifestyle changes
- Drugs?
**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
Polygenic Dysipidemia
- genes
- Lifestyle changes
** 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
What is familial hypercholesterolemia?
- mode of inheritance
- defect
- plasma lipids
- 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
What is familial combined hyperlipidemia?
- mode of inheritance
- defect
- plasma lipids
- 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
What is familial dysbetalipoproteinemia (type III hyperlipidemia)?
- mode of inheritance
- defect
- plasma lipids
- 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
What does a mutation in the cytoplasmic domain of the LDL receptor do?
- Decreased Internalization (receptor wont get taken in after binding)
What does a mutation in the membrane spanning domain of the LDL receptor cause?
Secretion of the Receptor (it won’t be held in membrane)
