Term
| What are some things that regulate cholesterol levels? |
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Definition
| Dietary chol and choleric intake, plasma cholesterol levels, hormones (glucagons and insulin), and bile acids. |
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Term
| What are the major control points in cholesterol synthesis? |
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Definition
| 1) HMG CoA Reductase activity (HMG CoA à Mevalonate step), 2) Rate of LDL receptor synthesis (intracellular chol controls transcription of this gene). 3) Rate of CE formation by ACAT (CE can be stored as droplets in the cell). |
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Term
| What is the most common lipid disorder? |
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Definition
| Familial Combined Hyperlipidemia. It affects 1 in 100. Almost always shows elevated plasma Apo B and disproportionately high LDL-C and VLDL-C. |
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Term
| True or false: Larger, more buoyant LDL's are more likely to be atherogenic? |
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Definition
| False. Smaller, denser LDL's are correlated with plaque build up. |
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Term
| How do we modify serum cholesterol levels? |
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Definition
| 1) Diet with low chol (recall 10-25% reduction), 2) Foods and additives (psyllium, soy, etc.) that lower chol, 3) Weight loss and exercise. 5) Drugs |
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Term
| How is HMG CoA reductase regulated? |
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Definition
| 1) Down-regulation of enzyme concentration. Cholesterol (end product) acts on "sterol-response elements" and exhibits transcriptional control. 2) Product inhibition (by mevalonate). 3) Covalent modification. Glucagon stimulates cAMP and represses HMG CoA reductase. Insulin activates synthesis. Phosphorylation also means faster degradation. 4) Hormonal control (thyroid). Phosphorylation and Tx mech's. |
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Term
| What are the two enzymes that DIRECTLY impact HMG-CoA activity. |
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Definition
| HMG CoA kinase (inactivates it) and HMG CoA phosphatase (activates it). |
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Term
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Definition
| They look like HMG CoA and serve as competitive inhibitors of HMG CoA reductase. |
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Term
| How do the two types of statins differ? |
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Definition
| Type 1 features a decalin ring. Type 2 features a fluorophenol group and a methylethyl group and have additional interactions with enzyme (more H-bonds). Type 2 (e.g. Lipitor) is thus more effective. |
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Term
| What is the result of statin action? |
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Definition
| Decreased HMG CoA reductase activity. Lower cholesterol synthesis. More LDL receptors made. More uptake from plasma. |
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Term
| True or false: More bile is excreted in patients taking lipitor. |
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Definition
| False. There is a larger PERCENTAGE of cholesterol in the bile because the intracellular chol concentration has increased due to more LDL receptors (even though there is less synthesis). |
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Term
| True or false: Cholesterol feedback inhibition of the reductase activity is not sufficient to completely inhibit cholesterol synthesis. |
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Definition
| True. Ubiquinones and dolichols need to be made, even in the presence of high cholesterol. Added regulation by product inhibition (i.e. mevalonate) is necessary to completely stop cholesterol synthesis. This is called multivalent control. |
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Term
| What are SRE's and SREBP's? |
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Definition
| Sterol response element (binding proteins). Sterols regulate transcription of many genes involved in lipid synthesis. |
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Term
| What are three sources of NADPH? |
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Definition
| G6P (G6PD), Malate (Malic enzyme), and 6-P-Gluconate (PGDH). |
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Term
| Give the gist of how sterols activate gene transcription. |
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Definition
| Sterol binds SREBP in ER. SCAP moves complex to Golgi where it is processed. N-terminal transcription factor is released from the SREBP and heads to the nucleus where it activates gene transcription by binding to SRE. Note that cholesterol blocks action of SCAP so that transcription can't happen when cholesterol concentration is high. |
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Term
| What are some pharmacological approaches to lowering plasma cholesterol? |
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Definition
| 1) Niacin (inhibits lipolysis in adipose tissue with G-protein coupled receptor; causes flushing), 2) Resins (bind bile acids in intestine and promote their excretion), 3) Statins (inhibit HMG CoA Reductase), 4) NR's (increase catabolism by starting reverse chol transport; PPAR-alpha transactivates these though HAD is also necessary), 5) Fibrates (stimulate LPL activity, reduce ApoCIII synthesis (increase clearance), and reduce VLDL production), 6) Chol absorption inhibitors |
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Term
| What drug is most effective at reducing TG levels? |
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Definition
| Fibrates. They also raise HDL-C levels. |
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Term
| What treatment avenue was recently stopped for excess mortality? |
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Definition
| CETP-targeting therapies aimed to raise HDL-C. The mechanism involves BLOCKING the transfer of CE's from HDL to ApoB LP's in exchange for TG's. The argument against this working is that the resulting CE-rich HDL's would be less effective at preventing plaque build-up. |
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