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95 Cards in this Set
- Front
- Back
2 sources of cholesterol:
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1. Diet
2. De novo synthesis in all cells |
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4 predominant tissues of Sterol biosynthesis:
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1. Liver
2. Adrenal cortex 3. Intestine 4. Reproductive tissues |
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Main sites where cholesterol functions: (2)
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1. Cell membrane component
2. CNS/brain myelinated structures |
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2 Direct Derivatives of Cholesterol
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1. Steroid hormones
2. Bile acids |
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8 Derivatives of Cholesterol INTERMEDIATES:
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-Vitamens D/E/A/K
-Carotenoids -Rubber -Plant hormones -Phytol chain of chlorophyll -Dolichols -Ubiquinone/Plastiquinone -Isoprene |
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Plant hormones (2):
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-Abscisic Acid
-Gibberellic acid |
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3 Most important derivatives of cholesterol to remember:
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-Steroid hormones
-Bile acids -Vitamin D |
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In what form is cholesterol in membranes?
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Unesterified - FREE
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What distinguishes free unesterified cholesterol from esterified?
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An -OH instead of Acyl
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What enzyme makes free cholesterol esterified?
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ACAT - Acyl-CoA Cholesterol Acyl Transferase
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What reaction does ACAT catalyze?
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Incorporates Fatty AcylCoA into Cholesterol w/ subsequent release of CoASH.
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When does ACAT work? Why?
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When membranes have too much free cholesterol ACAT esterifies it for intracellular storage or lipoprotein transfer.
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What is the function of cholesterol in membranes?
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Regulates fluidity and lateral mobility of proteins in the lipid bilayer.
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What is the storage form of cholesterol called?
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Cholesteryl Ester
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What type of molecule is cholesterol?
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Amphipathic
Nonpolar = 4 hydrocarbon rings Polar head = OH |
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How many carbons are in cholesterol?
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27
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What allows cholesterol to circulate in the blood?
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Apolipoproteins
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What is the carbon source for cholesterol synthesis de novo?
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Acetyl CoA
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3 Sources of AcCoA:
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1. FA beta-oxidation (mitochon)
2. Ketogenic amino acid oxidation (leucine/isoleucine) 3. PDH reaction |
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PDH Cofactors:
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-TPP
-Lipoamide -FAD |
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Reaction of PDH:
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Pyruvate -> AcCoA
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What enzyme catalyzes the COMMITTED STEP of Cholesterol biosynthesis?
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HMG-CoA Reductase
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What are the 4 major stages of cholesterol biosynthesis?
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0. Acetate
1. Mevalonate 2. Activated Isoprenes 3. Squalene 4. Cholesterol |
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What happens in Cholesterol biosynthesis Stage 1? Enzymes?
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AcCoA -> Mevalonate
-3 reactions -Thiolase, HMG-CoA Synthase, HMG-CoA Reductase |
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What is important re: first 2 reactions in Mevalonate synth?
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They are shared with Ketogenesis
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What is different about Ketogenesis vs. Mevalonate?
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Ketogenesis = mitochondria
Cholest Synth = Cytosol Hence dif. pools of enzymes |
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What are the enzymes shared by Ketogenesis & Mevalonate synth?
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-Thiolase
-HMG-CoA Synthase |
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In what tissue are the cytosolic and mitosolic pools found?
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Liver Parenchymal cells
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Why is Mevalonate synthesis so very important?
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Its 3rd reaction is the Commitment step of cholesterol biosynthesis
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Where do HMG-CoA reductase and subsequent reactions occur?
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Probably in peroxisomes.
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What occurs in the 1st reaction of Mevalonate synthesis? Enzyme?
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2 AcCoA condensation - releases one CoASH
-Via Thiolase |
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What is the product of Thiolase?
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Acetoacetyl-CoA
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What occurs in the 2nd reaction of Mevalonate synth? Enzyme?
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Acetoacetyl-CoA is condensed with another AcCoA
-Via HMG-CoA synthase |
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What is the product of HMG-CoA Synthase?
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HMG - b-hydroxy-b-methylgutaryl-CoA
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What occurs in the 3rd reaction of Mevalonate synth? Enzyme?
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CoASH released from far end of HMG-CoA; C=O reduced to CH2-OH; the protons donated by 2NADPH;
-Via HMG-CoA Reductase |
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Where is HMG-CoA reductase found, and how is it situated?
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-Integral - in the cell membrane
-Active site on cytosolic side |
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Product of HMG-CoA reductase is:
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Mevalonate
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What does Mevalonate get converted to? How?
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5-Carbon Activated isoprenes by Decarboxylation
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How many reactions and enzymes are needed for stage 2 of cholesterol biosynthesis?
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4 Reactions/3 enzymes
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Enzymes in 5C Activated Isoprene synthesis:
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1. Mevalonate 5-phosphotransferase
2. Phosphomevalonate kinase 3. Pyrophosphomevalonate Decarboxylase |
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Key thing to remember about stage 2 of cholest. biosynth:
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IT REQUIRES 3 total ATP
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What happens in the 1st reaction of stage 2?
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PO4 added to terminal carbon of Mevalonate - replaces the -OH created by HMGCoA reductase.
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What happens in the 2nd reaction of stage 2?
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Add another PO4 right onto the one added in reaction 1.
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What happens in the 3rd reaction of stage 2?
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Add another PO4 onto the beta carbon of pyrophosphomevalonate.
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What enzymes catalyze reactions 1 and 2?
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1. Mevalnt 5-phosphotransferase
2. Phosphomevalonate kinase |
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What enzyme catalyzes reactions 3 and 4 of stage 2?
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Pyrophosphomevalonate decarboxylase - same enzyme for both reactions.
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What occurs in reaction 4 of stage 2?
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Decarboxylation of carbon 1 and loss of PO4 from carbon 3
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What results from decarboxylating 3-Phospho-5-pyrophosphomevalonate?
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2 isomers:
-d3-isopentenyl pyrophosphate -Dimethylallyl pyrophosphate |
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What happens in Stage 3 of cholesterol biosynthesis? (in broad terms)
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Condensation of 6 activated 5-C isoprene units to make Squalene
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What substrate is used in stage 3?
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1 NADPH
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So substrates for:
-Stage 1 -Stage 2 -Stage 3 |
1 = 2 NADPH
2 = 3 ATP 3 = 1 NADPH |
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How many steps are entailed in Stage 3 of cholesterol synth?
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3 steps: C5 -> C10 -> C15 -> C30
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What enzymes are used in Stage 3?
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-Prenyl transferase (Rxns 1/2)
-Squalene synthase (Rxn 3) |
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What terms describe the nature of the 3 condensation reactions?
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Rxns 1/2 = head-to-tail
Rxn 3 = head-to-head |
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What are the intermediates in Squalene synthesis? How many Cs?
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1. Geranyl PPi (10 C)
2. Farnesyl PPi (15 C) |
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What is important about Farnesyl PPi?
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Used in post-translational protein modification
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Where does Farnesylation occur on proteins?
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C-terminal Cysteine residue
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What is unique about the final condensation of 2 Farnesyl PPi?
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-Head-to-Head
-Requires NADPH |
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What enzyme catalyzes the final step of stage 3?
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Squalene synthase
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How many carbons are in squalene? How many in cholesterol?
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Squalene = 30
Cholesterol = 27 |
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What needs to happen to squalene to make cholesterol?
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Cyclization to close rings
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In Squalene-Cholest conversion:
-How many reactions? -How many enzymes? -What substrates? |
-13 reactions
-11 enzymes -1 NADPH |
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How does Squalene cyclization get started?
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By activating it to Squalene Epoxide
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What enzyme makes Squalene 2,3-Epoxide?
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Squalene monooxygenase
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What does Squalene monooxygenase require?
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1 molecule of O2
1 NADPH |
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What enzyme cyclizes Squalene 2,3-Epoxide?
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Oxidosqualene cyclase
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What is the product of oxidosqualene cyclase action?
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Lanosterol
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What needs to happen to Lanosterol to make cholesterol?
(3 things) |
-Demethylation of 3 Carbons
-Reduce a double bond -Migrate another double bond |
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Substrates used in
-Stage 1 (HMG-CoA reductase) -Stage 2 -Stage 3 (squalene synthase) -Stage 4 (squalene monoxygnase |
-Stage 1: 2 NADPH
-Stage 2: 3 ATP -Stage 3: 1 NADPH -Stage 4: 1 NADPH |
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3 Inherited disorders of Cholesterol Biosynthesis:
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1. Chondrodysplasia punctata
2. Latherosterolosis 3. Smith-lemli-Opitz syndrome |
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What are the cholest biosynth inherited disorders associated with?
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Developmental malformities
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What is the problem in these disorders?
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Low cholesterol levels - lack of Hedgehog morphogens b/c they are made by post-transl. attachment of cholesterol.
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What is the main regulatory target in cholesterol biosynth?
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HMG-CoA Reductase
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3 levels of Regulating HMG-CoA reductase:
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1. Gene Transcription
2. Proteolysis 3. Phosphorylation |
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How is gene transcription of HMG-CoA reductase regulated?
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By SREBPs
Sterol Regulatory Element Binding Proteins |
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Where are SREBPs normally located? When is this the case?
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In the ER - when cholesterol is high (biosynthesis unnecessary)
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What happens to SREBPs when serum cholesterol gets low?
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SCAP (on ER membrane) senses low levels; it travels to Golgi w/ SREBP, then cleaves SREBP
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What part of SREBP gets cleaved; where does it go?
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N-terminus -> goes to the nucleus to bind the SRE for HMG-CoA reductase.
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What is SRE?
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Sterol Regulatory Element
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Result of SREBP binding to SRE?
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Activated transcription of HMG-CoA reductase hence increased cholesterol biosynth.
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What causes proteolysis of HMG-CoA reducatase?
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metabolites of cholesterol
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What 2 things do Cholesterol metabolites inhibit?
What do they ACTIVATE? |
-HMGCoA reductase (proteolysis)
-Extracellular uptake from LDL via receptor mediated endocytos. -Activates ACAT for esterifictn |
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Phosphorylated HMG-CoA is ____
Dephosphorylated HMG-CoA is ____ |
Phosph = inactive
Dephosph = active |
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What stimulates HMG-CoA phosphorylation/dephosphoryltn?
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Glucagon -> phosphorylate
Insulin -> dephosphorylate |
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How does glucagon stimulate phosphorylation of HMG-CoA red?
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Via AMP-activated protein kinase
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How does insulin stimulate dephosphorylation of HMG-CoA rd?
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Via HMG-CoA Reductase Phosphatase
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What are Statins?
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Competitive Inhibitors of HMG-CoA reductase
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What are the 4 Statins?
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-Compactin
-Simvastatin (Zocor) -Pravastatin (Pravachol) -Lovastatin (Mevacor) |
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What are Statins used for?
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To treat familial hypercholesterolemia
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What pleiotropic effect is exhibited by statins?
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Improved endothelial function via increased ENOS activity -
is how Viagra was discovered. |
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End product of cholesterol is:
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Bile acids
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Where are bile acids made? From what?
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In liver from cholic acid
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What is cholic acid?
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Derivative of Cholesterol that is more soluble - 24 Carbons and 3 OH
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What is the function of bile acids?
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To emulsify fats in prep for pancreatic lipase
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What happens to bile acids after release from gallbladder to intestine?
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Reabsorbed - synthesis is not enough to meet physiolog demands.
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