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29 Cards in this Set
- Front
- Back
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Describe step 1 in cholesterol biosynthesis.
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1. Acetyl CoA is synthesized to HMG-CoA by HMG CoA synthase
**occurs in cytoplasm 2. HMG CoA is converted to Mevalonate by HMG REDUCTASE. -rate limiting step -highly regulated *Uses NADPH Mevalonate is only used in cholesterol production. ***This step and all after occur on smooth endoplasmic reticulum |
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Describe step 2 in cholesterol biosynthesis.
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1. Mevalonate to active isoprenoids
*uses 3 ATP *produces CO2 2. Then converted to squalene (several condensation steps) *uses NADPH |
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Describe step 3 in cholesterol biosynthesis.
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Squalene to lanosterol (ring structure, parent sterol)
*uses O2 and NADPH |
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Describe step 4 in cholesterol biosynthesis.
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Lanosterol is converted to cholesterol (19 steps)
*uses O2, NADPH *minus three methyl groups |
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How is HMG CoA Reductase activity controlled?
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The amount of and activity of the enzyme is regulated.
Fasting state: Glucagon reduces ACTIVITY indirectly through post translational phosphorylation. Fed State: Insulin increases activity by indirectly causing dephosphorylation of the enzyme through a protein phosphatase. |
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How is amount of HMG CoA Reductase controlled?
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1. HMG CoA Reductase has a cholesterol binding domain.
-high cholesterol will bind the enzyme and cause it to self degrade. 2. Normal or high cholesterol decreases production of the enzyme by blocking the enzyme that cleaves SREBP (a regulatory binding protein, which binds to promoter. SREBP is in the ER membrane. 2. Low cholesterol, the protease is no longer repressed which allows pre SREBP to be cleaved into its active form. SREBP then binds to the promoter allowing transcription to take place. A similar mechanism is present for the LDL receptor. SREBP will increase the LDL receptor. High intracellular cholesterol inhibits synthesis of cholesterol and decreases uptake of cholesterol from the extracellular environment. |
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What is ACAT?
What is LCAT? |
1. acylCoA:cholesterol acyltransferase, storage
-esterification makes the cholesterol more lipophilic and allows for storage in a droplet. ***esterified form is not a signaling molecule. 2. Lecithin:cholesterol acyltransferase, for transport |
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What does 7-alpha hydroxylase do?
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1. Rate limiting and committed step to bile synthesis. This enzyme is exclusively found on ER of liver cells.
**NADPH, O2, and VITAMIN C are required. |
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How is 7-alpha hydroxylase regulated?
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FEED FORWARD: Cholesterol binding to Liver LXR (binds to nuclear receptor=induction of enzyme production)
FEED BACK INHIBITION: Bile acids binding to liver FXR (promoter repression) |
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What happens during cholesterol uptake?
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1. LDL+cholesterol ester (CE) bind to LDL receptor. LDL receptor + package is endocytosed.
-receptor is recycled. 2. CE is lysosome/late endosome 3. Transported to golgi by NPC-1 (mediated transfer) 4. It is then: stored ACAT, used for /metabolism/synthesis, or released via LCAT. |
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Describe HDL
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1. Contain CE
2. Lecithin 3. Unique proteins 4. LCAT (for esterifying free cholesterol in cell membranes) HDL function is enhanced by ATP binding cassette protein (ABCA1) transport called cholestero efflux regulatory protein (CERP). CERP is activated by apolipoprotein A1 which is part of HDL CERP pumps cholesterol across membrane, LCAT esterifies. Esterified cholesterol in HDL is transported to liver. |
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How does the cell decrease free unesterified cholesterol?
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1. Uses for synthesis/metabolism
2. Stores through ACAT 3. Transfers to HDL via CERP, directed by GOLGI. (REVERSE CHOLESTEROL TRANSPORT) |
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How does the cell increase free unesterified cholesterol?
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1. Endocytic uptake through LDL, macrophage uptake of cholesterol containing lipoproteins, non receptor mediated pathways (diffusion of free cholesterol from lipoproteins)
2. Biosynthesis 3. Hydrolysis of cholesterol esters (cholesterol esterase |
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Describe LDL-LDL receptor endocytosis?
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1. LDL receptor binds to LDL apoprotein B100. LDL+ receptor is endocytosed into lsysosome/late endosome.
-Receptor is recycled to membrane. -CE is hydrolyzed to free cholesterol and is then transported to golgi by NPC-1. -free cholesterol has its regulatory effects on cholesterol synthesis and LDL receptor synthesis (see other slides) -Free cholesterol binds to LXR which induces CERP. |
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What is the mechanism of statins?
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1. Competitive inhibitos of HMG-CoA reductase.
-Prevents synthesis of vLDL which become LDL -Also increase HDL by increasing apolipoprotein A1 |
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What are bile acid sequestering resins and how do they work?
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Drugs like cholestyramine, colestipol, colesevelam) bind to bile acids in the GI and prevent their reuptake. This prevents inhibition of 7 alpha hydroxylase which causes cellular cholesterol to be used for bile acids. This will eventually lead to a decrease in intracellular cholesterol and a decrease in serum cholesterol.
-can cause increased triglycerides and abdominal fullness. Apple pectin does the same thing. |
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What nicotinic acid and how do it work?
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AKA niacin or vitamin B3
-precursor for NAD and NADH Action: Increases HDL, decreases LDL. mechanism is not well understood -may decrease FA release from adipose tissue and may inhibit production of vLDL SE: Flushing, HA, dizziness, blurred vision -Long term use: liver damage Monitor for AST and ALT |
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What are fibrates and how do they work?
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1. Decrease triglyceride and increase HDL. Little or no effect on LDL
2. Action: Unknown |
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What ezetimibe (Zetia) and how does it work?
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Action: decreases cholesterol absorption. Binds to NPCL1 which decreases cholesterol uptake from intestinal lumen.
SE: HA, diarrhea, myalgia, liver effects. -monitor liver and kidney function. |
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What are lipoproteins composed of?
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1. Apolipoprotein
2. Cholesterol(s) 3. Phospholipids 4. Triacylglycerols Monolayer structure |
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Rank lipoproteins based on protein/lipid content.
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Percent of protein:
HDL>LDL>VLDL>Chylomicrons Percent triacylglycerols: Chylomicrons>VLDL>LDL>HDL Percent cholesterol: LDL>HDL>VDLD>Chylomicrons HDL: alpha lipoproteins LDL: Beta lipoproteins IDL: Between |
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What is the function of VLDL
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1. Transport endogenously synthesized triacylglycerol from the liver to extrahepatic tissues.
Also contains B100 2. Transport of liver generated cholesterol for LDL VLDL matures by acquiring apo CII and APO E proteins from HDL. Eventually returns returns to HDL. Goes from VLDL to IDL to LDL Catalyzed by LPL which is activated by apolipoprotein CII. LPL is located on endothelial surfaces. LPL hydrolyzes transported triacylglycerol. Insulin increases LPL function. |
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What does apo B100 do?
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Apo B100 on LDL binds to LDL receptor
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What does apo E do?
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-Binds to liver receptor to deliver cholesterol.
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What do genetic defects in the apo E ligand do?
Apo B100 receptor defects? |
Elicit type III hyperlipidemia
Type II hyperlipidemia |
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What is Wolman disease?
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It is a defect in the lysosomal cholesterol ester hydrolase (ACEH) that cleaves cholesterol ester from LDL to free cholesterol.
-CE builds up in membrane core and destroys cell. Rarely survive first year, hepatosplenomegaly and necrotic adrenal cortex. |
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What is Niemann Pick C disease?
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Defect in NPC 1 that mediates the intracellular traffic of free cholesterol. Accumulation of free cholesterol results in loss of motor skills and nuerologic decline. Hepatosplenomegaly.
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What is Tangier disease?
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HDL is very low, results in marked reduction of plasma cholesterol and phospholipids.
-cholesterol deposits pathologically -engorged macrophages DEFECT IN CERP S/S: Hepatoplenomegaly, lymphoreticular cholesterol accumulation. -orange colored tonsils -peripheral neuropathy and muscle weakness. |
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Type II hyperlipidemias
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Defect in B100 receptor, increases LDL plasma concentrations.
-Familial hyperlipidemia |
