cholsterol metabolism Pharm 11-6-12

Hmg coa reductase regulation intermediate term

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HMG CoA reductase regulation intermediate term Reversible Enzyme Phosphorylation Increases activity when Insulin is present (a signal of energy intake) Decreases activity during fasting ( glucagon ) In this way cholesterol synthesis is again integrated into broader energy metabolism in a circadian rhythm Weaker statins are more potent when dosed at night
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An important summary slide ON Substrate Insulin Energy OFF Glucagon Mevalonate Cholesterol LDL uptake Statins
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Mevalonate to Isopentyl pyrophosphate Mevalonate 5-pyrophosphoMevalonate Isopentyl pyrophosphate ATP
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Isomerase Isopentyl pyrophosphate dimethylallyl pyrophosphate
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Can be attached to proteins to serve as lipid anchor With many downstream effects Isopentyl pyrophosphate dimethylallyl pyrophosphate Geranyl pyrophosphate
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More dull steps Geranyl pyrophosphate Isopentyl pyrophosphate Farnesyl pyrophosphate Can be attached to proteins to serve as lipid anchor
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Not Just cholesterol
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Squalene Farnesyl pyrophosphate Farnesyl pyrophosphate
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Squalene Lanosterol O OH
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Finally (after 20 additional steps)
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When cellular cholesterol rises Cell membrane cholesterol levels rise. Membrane bound enzymes sense the change. Enzyme degradation Long term regulation
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Most cells can acquire cholesterol from blood as LDL Elevated cholesterol reduces LDL receptor expression.
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Regulation is complex Multilevel & Redundant Elegant You don’t need to memorize this You should understand it LDL Receptors & HMG-CoA Reductase More bile acid synthesis More efflux protein
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2. Which statement is FALSE? All of the carbon in c... HMG CoA reductase ... Cholesterol synthesis .. Most cells are able to... 25% 25% 25% 25% 1. All of the carbon in cholesterol is derived from acetyl-CoA. 2. HMG CoA reductase catalyzes the rate limiting reaction in cholesterol synthesis. 3. Cholesterol synthesis in cells is constant and unregulated. 4. Most cells are able to synthesize cholesterol as needed
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Cells try to avoid over- accumulation of cholesterol Regulation of LDL receptor Regulation of HMG CoA reductase Transport to HDL
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Liver & gut can remove cholesterol as lipoproteins Contain relatively little cholesterol to triglyceride Cholesterol is not removed from the body, but from the tissue of origin only.
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