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1. General structure of lipoproteins? (perimeter - 3, core - 3)
2. How does triglyceride take up differ from cholesterol/FSV take up?
3. How are lipoproteins isolated?
4. Why can't cholesterol travel in blood by itself? (2) How is it transported then?
5. What are the functions of apolipoproteins? (2)
1. Perimeter - amphiphilic proteins, free cholesterols, phospholipid monolayer. Core - TGs, CEs, FSV
2. Triglyerides' FFAs are cleaved off --> LPL/HL while cholesterol/FSV is taken up by peripheral tissue via endocytosis (LDL-Receptor)
3. Via ultra-centriguation (by density)
4. Not H2O-sol and can easily disrupt membrane function. In LDL and HDL as CEs.
5. (1) stabilize lipoproteins throughout transport in blood (2) stimulate enzymatic functions & receptor binding
What do the following apoproteins do?
1. A1 (3)
2. B48, B100 (2)
3. CII, CIII (2)
4. E (1)
5. What is the reservoir of CII and E?
1. A1 - activates LCAT, receptor binding, found mostly on HDL (has been found on chylomicrons too)
2. B49, B100 - receptor binding (LDL-R) in peripheral tissues and liver, designates TAG delivery lipoproteins
3. CII, CIII - regulate LPL. CII activates LPL, CIII inhibits it.
4. E - receptor binding (hepatocytes recognize ApoE on chylomicron remnants and endocytose it).
1. What do chylomicrons and HDL exchange? 2
2. What do VLDL and HDL exchange? 3
3. What happens to cholesterol metabolism in cell when LDL is uptaken? (3)
4. What is LCAT and who has it? What does it do to HDL? (3)
4.5 What substrates does LCAT use?
5. What does CETP do? (4) What happens when its pharmacologically inhibited?
1. HDL gives VLDL ApoCII and ApoE. ApoCII is returned to HDL.
2. ApoCII and ApoE (CEs thanks to CETP when TAG is removed from VLDL). ApoCII and ApoE returned to HDL.
3. HMG CoA reductase is inhibited, decreased expression of LDL receptors, endocytosed cholesterol can be esterified by ACAT in cell.
4. LCAT (lecithin-cholesterol acyltransferase) - HDL picks up free cholesterol and esterifies it using LCAT. It also turns (1) nascent HDL into mature HDL --> (2) increases storage capacity of HDL (3) increases capacity for HDL to accept cholesterol from peripheral tissues
4.5 LCAT uses phospholipid (lecithin) + free cholesterol --> cholesteryl ester
5. Trades triglycerides (from VLDL/chylo) for cholesteryl ester (from HDL) (1) Increases storage capacity of HDL (2) Increases LDL cholesterol (3) Decreases HDL. HDL-C increases
1. What does MTP stand for?
2. What does it do? (2)
3. Where is it found? (cell) (tissues)
4. Who lacks functional MTP? What does this lead to clinically? (2)
5. Main function of APoB containing particles?
6. Enzyme responsible for coding ApoB48? Mice?
1. Microsomal triglyceride transfer protein
2. (1) Transports lipids from ER membrane to ApoB (2) enables proper folding and translocation of apoB and secretion into Space of Disse FOR APOB CELLS!!
3. Found in lumen of ER. In liver (VLDL) and intestine (chylomicrons)
4. Abetalipoproteinemia --> low plasma TG and cholesterol.
5. Primarily (1) deliver TGs to muscle cells for fuel/adipocytes for storage (2) secondary - to assist with reverse cholesterol transport (HDL transfers CEs to VLDL).
6. Apobec-1. Mice have apobec-1 in intestines AND liver, so its hard to differentiate.
1. Where is LPL found?
2. Associated with what tissues? (esp which 3 tissues?)
3. What does it do? Products? (3)
4. What is it activated/inhibited by? (2)
5. What anchors LPL to vascular endothelium? What happens in absence of this thing?
- 1. LPL is found in non-hepatic tissues
- 2. Associated with endothelial surface esp in adipose tissue, muscle, heart.
3. Hydrolyzes TAGs --> FAs, DAGs, and glycerol
4. Activated by ApoCII. Inhibietd by ApoCIII
5. Protein GPIHBP1. Lipemia.
1. What happens when LDL-R is defective?
2. From epid standpoint, what is associated with less coronary artery disease? 3
3. What is established to reduce CAD risk in patients with dyslipidemia? (1) Strong evidence (2) Not established? (6)
1. Hypercholesteremia (Familiar hypercholesterolemia)
2. High HDL, low LDL/TG
3. LDL-C. HDL-C, Triglycerides. Lp(a), oxidized LDL-C small dense LDL, homocysteine, CRp, coagualbility.
Describe mech of HDL/LDL and heart disease
- 1. LDL goes into vascular endothelium
- 2. Becomes oxidized
- 3. Activates differentiation of LDL --> macrophage recruitment
- 4. HDL takes cholesterol away from fatty streak back to liver
- 5. Increasing ApoA1 containing particles an prevent progression of formation or you can reverse atheroma.
What are therapeutic approaches to treatment of dyslipidemia? (6)
- 1. HMG CoA reductase inhibitors (Statins)
- 2. Bile salt sequestrants
- 3. Inhibition of cholesterol absorption (Ezetimibe - inhibits NP1LP1
- 4. Knockdown of apoB with ASO
- 5. PCSK9 inhibition
- 6. Niacin
1. What happens to HMG CoA reductase, LDL receptor, and ACAT when IC cholesterol increases?
2 When IC chol decreases
3. What do statins do? 1-->4
4. How do they affect ubiquinone?
5. What do bile salt sequestrants do?
6. How does one knockdown ApoB with ASO?Name of drug?
7. What does inhibition of PCSK9 do? What does the molecule usually do?
8. How does niacin work?
1. HMG CoA decreases, LDL R decreases, ACAT increases
2. HMG CoA increases, LDL-R increases, ACAT decreases
3. Competitively inhibit HMG CoA reductase --> depletion of IC cholesterol --> increase LDL-R --> clears LDL/choletserol from blood.
4. Inhibits ubiquinone which is bad.
5. Promote loss of bile salts from enterohepatic circulation by increasing LDL clearance from plasma.
6. ASO = antisense oligonucleotide that causes recruitment of RNAse H --> breaks down mRNA tx so it doesn't get translated into ApoB. Mipsomersin inhibits MTTP.
7. PCSK9 usually signals degradation of LDLR. Inhibiting PCSK9 increases LDL-R concentration --> increasing LDL clearance from plasma.
8. Niacin will increase HDL.
Less TG in hepatocyte --> less TG for MTP/ApoB --> less VLDL secretion --> less lipolysis to LDL --> decreases serum LDL --> reduces HDL clearance.
1. What is Lp(a)
2. What is it associated with
1. LDL-like particle covalently bound to ApoA through single disulfide bond.
2. Associated with increased risk of CV risk factors.