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69 Cards in this Set
- Front
- Back
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How are cholesterol and cholesterol esters made soluble?
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By lipoproteins
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What are the 2 functions served by proteins in lipoproteins?
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1. Solubilize lipids
2. Cell-targeting signals |
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Density/diameter of Chylomicron:
Richest in: Apolipoproteins: |
Density <1.006
Diameter 75-1200 nm Rich in Triglyceride (85%) Apo-A Apo-B48 *acquires C/E* |
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Density/diameter of VLDL:
Richest in: Apolipoproteins: |
Density 0.95 - 1.006
Diameter 30-80nm Rich in Triglyceride (50%) Apo-A Apo-B100 Apo-C |
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Density/diameter of IDL:
Apolipoproteins: |
Density 1.006-1.0019
Diameter 25-35nm Apo-B100 Apo-C Apo-E |
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Density/diameter of LDL:
Richest in: Apolipoproteins: |
Density 1.0019-1.063
Diameter 18-25 nm Rich in Cholesteryl Ester Apo B100 |
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Density/diameter of HDL:
Richest in: Apolipoproteins: |
Density 1.063-1.210
Diameter 5-12 nm Rich in Protein Apo-A1 Apo-C Apo-E |
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Where are chylomicrons assembled? Released?
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Assembly = intestine
Release = Enterocytes |
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What is the first step in chylomicron metabolism?
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Hydrolysis by LPL (lipoprotein lipase) at extrahepatic tissue.
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What tissues mainly have LPL?
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Adipose and Skeletal muscle
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What are the products of LPL hydrolysis of chylomicrons?
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FFA + monoacylglycerol
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What happens to the hydrolyzed products of chylomicron?
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-FFA Storage (fat cells)
-FFA B-oxidation (muscle) -Monoacylglycerol is sent to liver for gluconeogenesis. |
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Where exactly is LPL located?
How is it held in place? |
On the endothelial surface of blood vessels in fat/muscle.
-Held in place by Heparan Sulfate proteoglycans. |
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What is necessary to activate LPL?
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Apo-CII
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So how is it that chylomicrons can activate LPL?
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They acquire Apo-CII and Apo-E from HDL remodeling.
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How is LPL activated in adipose tissue? Under what conditions?
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By INSULIN - in ANABOLIC condtns
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What happens in step 2 of chylomicron metabolism (to the remnants of LPL hydrolysis)?
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Residual triglycerides & dietary cholesterol delivered to liver.
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How does the liver take up chylomicron remnants? (2 receptors)
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-LDL receptor
-Hepatic lipase |
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What is required for LDL receptor uptake?
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Apo-E (acquired from HDL remodeling)
(Apo-B100 works too, but not as high affinity as Apo-E) |
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What is required for Hepatic Lipase activity?
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Apo-E
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What happens after hepatic uptake of chylomicron remnnats?
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Endocytosis in lysosomes; released cholesterol has 3 fates.
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What are the 3 fates of cholesterol released in hepatocytes?
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1. Form bile acids
2. Secreted into bile as such 3. Incorporate into nascent lipoproteins (HDL) |
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How are both LPL and Hepatic lipase bound to cell membranes?
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By Heparan Sulfate Proteoglycans.
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Why are VLDLs made?
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When triglycerides are in excess VLDLs provide a way to export them from the liver.
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So VLDLs are made and secreted from?
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Liver/Hepatocytes.
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What causes excess triglyceride? (3 things)
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1. Lipogenesis
2. Plasma FFA 3. Chylomicron remnants taken up by LDL/Hepatic Lipase |
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What does VLDL metabolism consist of?
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Basically same as Chylomicrons
Step 1: Apo-CII activates LPL; releases FFA to tissues Step 2: VLDL remnant taken up by liver LDL receptor. |
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What is the VLDL remnant called?
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IDL
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What happens to IDL after hepatic endocytosis into lysosomes?
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It goes to the 3 fates of released cholesterol.
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What happens to IDL if it bumps into hepatic lipase?
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Hepatic Lipase binds and removes Apo-E, which results in LDL
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What 2 things does Heparan Sulfate bind?
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-IDL (vldl remnant)
Does this principally -Chylomicron remnant |
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What 2 things can LDL do?
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1. Bind LDL receptor (but low affinity b/c only has Apo-B100
2. Go to peripheral tissues |
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What does LDL do at peripheral tissues?
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Binds the LDL receptor and gets endocytosed into lysosomes.
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What is the purpose of LDL at peripheral tissues?
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Regulation of de novo cholesterol synthesis
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What is the consequence of LDL receptor having a much higher affinity for ApoE than ApoB100?
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IDL (as ApoE) has a much shorter T1/2 than LDL (only ApoB100) and more gets taken up at liver.
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What regulates whether LDL will be taken up by the liver of peripheral cells?
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The amount available.
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Where does HDL originate?
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-Liver
-Small intestine |
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What is the initial form of HDL described as? Why?
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Nascent/discoidal - b/c it is mainly protein w/ little cholesterol or cholesteryl esters.
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How does cholesterol get incorporated into HDL?
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By ABCA1
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What is ABCA1?
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ATP-Binding cassette transporter
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How exactly does ABCA1 work?
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It delivers cholesterol to Apo-A1
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How is Mature HDL formed?
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By the addition of cholesteryl esters to ApoA1 - done via LCAT.
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What are the 2 functions of HDL?
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1. Lipoprotein remodeling
2. Cholesterol transport to liver/cells for steroid hormone synthesis. |
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What 2 molecules on HDL are responsible for lipoprotein remodeling?
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PLTP: phospholipid transfer protein
CETP: Cholesteryl ester transfer protein |
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What does PLTP do?
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Transfers phospholipids and cholesterol INTO HDL.
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What does CETP do?
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Removes Cholesteryl esters FROM HDL.
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What molecule allows uptake of HDL by liver/adrenal gland for steroid hormone synthesis?
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SR-B1 - scavenger receptor b1
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What is the main purpose of LCAT?
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Synthesis of cholesteryl esters from free cholesterol in plasma lipoproteins.
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Where is LCAT made?
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Liver cells
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Where does LCAT act?
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In circulation (blood) on HDL.
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What is the mechanism of LCAT?
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Transfers a fatty acyl residue from lecithin (phosphatidyl choline) to free cholesterol.
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What are the 2 products of the LCAT reaction?
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Cholesteryl Ester
Lysolecithin |
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Why does LCAT have a high preference for HDL?
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B/c it is activated by ApoA1 which is only on HDL.
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What are the steps in HDL circulation?
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1. Apo A1 (depleted HDL) picks up C from periph. cells
2. Nascent HDL picks up CE from circulation via LCAT 3. Mature HDL binds SRB1 on liver/adrenals to make steroid hormones. Depleted HDL recycles |
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Is there a normal ref range for lipids in people?
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No; widely varies.
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What is the most important disorder of plasma lipoproteins?
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LDL receptor disorder
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What is LDLreceptor deficiency called, and what results?
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Familial hypercholesterolemia - can't take up cholesterol from IDL/LDL via the LDL receptor.
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List 3 Clinical characteristics of Famlial hypercholesterolemia:
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1. High plasma LDL levels
2. LDL-derived cholesterol deposts in tendons/skin/arteries 3. Autosomal dominant |
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What genetic effect results from FH being autosomal dominant?
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Dosage - homozygotes get it worse than heterozygotes.
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Occurence of FH-heterozygotes?
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1/500 - most common inborn error of metabolism!!
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Occurence of FH-homozygotes?
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1/1 million
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Who is at higher risk of having coronary heart symptoms - m/w?
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Men - women have protective effects via estrogen
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What is an Atheroma?
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Atherosclerosis in coronary arteries
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What is Atheromas characterized by?
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1. Accumulated Cholesteryl esters in foam cells
2. Smooth muscle proliferation 3. Fibrosis |
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Why is LDL receptor deficiency so bad?
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B/c it is the main way that nonhepatic cells obtain cholesterol for membranes.
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How do cells get cholesterol via LDL?
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By receptor-mediated endocytosis
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What component of LDL does the LDL receptor bind?
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Apo B100
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What 3 things does oversupply of cholesterol in nonhepatic cells result in?
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1. Inhibited HMG-CoA reductase
2. ACAT activation 3. Inhibited synthesis of LDL receptor. |
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What happens to cholesterol if it accumulates in a nonhepatic cell?
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-ACAT esterifies it w/ long chain FA
-Stored as cholesteryl ester droplets |
