cholsterol metabolism Pharm 11-6-12

They make soluble cholesterol and fats they are

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They make soluble cholesterol and fats They are absorbed by specific transport proteins They are returned to the liver in the portal blood There is an obligate loss in the stool
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Dietary phytosterols They are present in vegetables They inhibit cholesterol absorption by competitively blocking uptake by NPC1-L1 They are removed from the enterocyte by a specific transporter and all but minimal quantities are excreted in the stool
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1. Which of the following statements is FALSE? F ree chol e sterol is le.. Bile acids are absorb.. Vegetables co ntain . . . 33% 33% 33% 1. Free cholesterol is less hydrophobic than cholesterol esters. 2. Bile acids are absorbed with cholesterol but are not incorporated into chylomicra. 3. Vegetables contain essentially no cholesterol.
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Relevant Anatomy & Physiology Gut dietary cholesterol fecal cholesterol Blood Bile Liver Lymph TISSUES TISSUES
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Most cells can acquire cholesterol from blood as LDL Low cholesterol levels stimulate LDL receptors. LDL uptake reduces receptor expression. PCSK9 PCSK9 PCSK9 degrades receptor
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LDL receptor Binds LDL & other particles (next lecture) Synthesis is increased when cells need more cholesterol Expression is decreased when cells need less Defects in the receptor or its regulation have profound effects on serum lipid levels Degraded by PCSK9
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Storage & Synthesis we are not dependent on LDL Endoplasmic Reticulum: synthesis Lipid Droplets: Storage as ester
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Cholesterol Stored as Ester ACAT localized on ER. Sterol Sensing mechanism determines activity. Esters can be hydrolyzed as needed by Lysosomal Acid Lipase (LAL) in lipid droplet.
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Cholesterol Synthesis 18 Acetyl-CoA + 14 NADPH + 14 H + + 5 H 2 O + 18 ATP + O 2 ---> Lanosterol (a precursor of cholesterol) + 14 NADP + + 18 CoA-S-H + 18 ADP + 6 P i + 4 PP i + 6 CO 2 Requires substantial energy Numerous enzymes Careful regulation
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Major Steps in Synthesis Building block is acetyl CoA Energy is consumed Rate Limiting Step is HMG-CoA Mevalonate Defects are lethal oxysterols 20 steps
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How to get from point A to point B CoA Acetyl-CoA
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Reaction 1: thiolase CoA CoA CoA Acetoacetyl-CoA Acetyl-CoA
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As H2 O Reaction 2: HMG CoA Synthase CoA CoA CoA 3 hydroxy 3 methyl glutaryl CoA Acetoacetyl-CoA Acetyl-CoA
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Reaction 3: HMG CoA Reductase CoA 3hydroxy 3 methyl glutaryl CoA Mevalonate 2 NADPH CoA
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Rate Limiting Step
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HMG CoA Reductase Rate Limiting Step CoA, HMG, NADP Localized to ER Sterol sensing domain Activated when ER cholesterol is lower Degraded when ER cholesterol is higher
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Inhibitors of HMG CoA Reductase Lovastatin CH 3 HO O O H O O H 3 C H H 3 C
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HMG CoA Reductase Inhibitors
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HMG CoA reductase regulation short term Competitive inhibition Mevalonate Statins (HMG CoA reductase inhibitors)
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Reversible Phosphorylation induced by hormones
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