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18 Cards in this Set
- Front
- Back
Hyperlipidemia
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Hyperlipidemiais a group of disorders of elevated blood lipids that can include highcirculating concentrations of cholesterol (hypercholesterolemia), triglycerides(hypertriglyceridemia), and free fatty acids (and any combination thereof). |
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Lipoprotein structure and composition
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lipoproteinsare spherical macromolecular complexes of lipids and specific proteins (apolipoproteins) lipoproteinstransport hydrophobic neutral lipids (cholesterol esters and triglycerides)throughout the body |
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Lipoprotein structure and composition
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lipoproteinsare categorized based on density ... dictated by their lipid composition eachclass of lipoprotein also has a distinct complement of apolipoproteins (CM=B48, VLDL&LDL=B100) |
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Lipoproteins
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ApoB-containinglipoproteins are assembled and secreted by the intestine (CM) and liver (VLDL) MTP(microsomal triglyceride transfer protein) transfers triglycerides andcholesteryl esters to the nascent apoB lipoproteins (CM and VLDL) apoB lipoprotein assembly and secretionis regulated by cellular availability of cholesteryl esters and triglycerides |
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Regulation of cholesterol metabolism
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LDL receptor mediated endocytosis of LDL particles results in increased intracellular free cholesterol concentration Regulatory proteins at the Endoplasmic Reticulum sense this increase in free cholesterol, triggering changes in gene expression and enzyme activity (1,2,3) to ensure that free cholesterol levels return to normal 1. HMG CoA reductase expression is downregulated. ( Involved in cholesterol synthesis) 2. Acyl CoA cholesterol acyltransferase (ACAT) activity is increased (ACAT esterfies cholesterol for safe storage within cytosolic lipid droplets) 3. LDL recetor expression is downregulated to prevent further LDL uptake |
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How does hyperlipidemia lead to CVD?
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-CVD generally a consequence of atherosclerosis -Atherosclerosis: plaques composed of lipids develop within the artery wall -LDL, VLDL, and chylomicrons can all contribute to development of atherosclerosis -- LDL is the most atherogenic lipoprotein HDL --> plaque repression; low HDL associated with increased disease risk |
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Anatomy of an atherosclerotic Plaque
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Infiltrating monocyte macrophages Smooth muscle cells foam cells Necrotic lipid core -LDL that enters sub-endothelial space becomes oxidized and promotes monocyte chemotaxis and activation -oxLDL prevents monocyte egress from sub endothelial space -oxLDL is taken up by resident monocyte-macrophages (foam cells) -continued uptake of oxLDL by foam cells leads to their necrosis (necrotic core) -VLDL and chylomicrons can also contribute to foam cell formation and plaque progression |
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Pharmacological treatment of hyperlipidemia
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-lowers LDL, increase HDL, lower triacylglycerides FIBRATES: -lower LDL, increase HDL, lower triacylglycerides NIACIN -lower LDL, increase HDL, lower triacylglycerides Bile Acid Sequestrants -lower LDL, increase HDL, minimal Cholesterol Absorption inhibitors - a little bit of everything |
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HMG CoA reductase
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-alsoknown as statins, inhibit the rate-limiting enzyme of cholesterol synthesis - statins areanalogs of HMG, the precursor of cholesterol, and are competitive inhibitors ofHMG CoA reductase -statinsundergo significant first-pass metabolism in liver, so their dominant effect ison hepatocytes byinhibiting cholesterol synthesis in the liver, they deplete intracellularcholesterol, leading to a compensatory increase in hepatocyte LDL receptorexpression ... increased clearance of circulating cholesterol |
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HMG CoA reductase side effects
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liver side effects because or large first-pass metabolism in the organ Myopathy (disintegration of muscles (rare but serious) statins are contraindicated during nursing, don't use in children |
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Fibrates
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-thefibrates (fenofibrate, gemfibrozil) are peroxisome proliferator-activatedreceptor a (PPARa) agonists -inliver, PPARaactivation increases apoAI and ApoAIIsynthesis in hepatocytes which leads to increased circulating HDL (reversecholesterol transport) -PPARaactivation also increases fatty acid oxidation, thereby decreasing triglyceridesynthesis and VLDL production (decreased circulating triglycerides) andsubsequent conversion to LDL (decreased circulating cholesterol) inmuscle vascular beds, PPARa activation increases lipoprotein lipaseexpression and increases fatty acid oxidation ... increased uptake andutilization of fatty acids from VLDL and chylomicrons (decreased circulatingtriglycerides) |
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Fibrates in my own words
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Fibrates --> activate PPARa --> inc. in apoAL, ALL synthesis in hepatocytes --> Inc. Plasma HDL -->inc cholesterol efflux from the cell Fibrates --> Activation of PPARa --> increase in Fatty acid oxidation in hepatocytes --> decrease in triglyceride synthesis -->decreased VLDL assembly and secretion --> decreased lasma triglycerides Fibrates --> inc lipoprotein lipase in muscle vascular beds --> inc. fattcy acid uptake in muscle cells and increase fatty acid oxidation in muscle cells --> decreased plasma triglycerides |
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Niacin
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-vitamin b3 - potent inhibitor of lipolysis in adiocytes -Niaspan XR -reduced FA flux to liver -->reduced VLDL secretion by hepatocytes -Niacin also increase HDL *not sure how* -cutaneous flushing as a side effect |
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Niacin: mechanism of action
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BINDS TO GPCR ON ADIPOCYTES WHICH RESULTSIN DECREASED LIPASE ACTIVITY THIS RESULTS IN DECREASED FREE FATTY acids flux to the liver Thisreduces hepatic triglyceride synthesis, thereby limiting VLDL production andsubsequent LDL production |
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Bile Acid Sequestrants
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-cholestyramine, colestipol, colesevelam (anion exchange resins that bind negatively charged bile acids and bile salts in the small intestine - resin/bileacid complexes are excreted in the feces, thus preventing the return of bileacids to the liver through enterohepatic circulation decreasedbile acid concentration triggers hepatocytes to convert more cholesterol tobile acids, thereby decreasing hepatocyte cholesterol content ... leading to acompensatory increase in heptocyte LDL receptor expression ...increased clearance of circulating cholesterol |
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Bile Acid Sequestrants in my own words
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Bile Acid Sequestrants form insoluble complex with the bile acids and salts preventing their reabsorption from the intestine (go to feces) This forces hepatocytes to convert more cholesterol into bile and salts |
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Cholesterol absorption inhibitor |
-only drug: ezetimibe - toselectively inhibit the absorption of cholesterol (both dietary and biliary)from the small intestine by inhibiting the sterol transporter Neimann-Pick C 1L1 (NPC1L1) Theresulting decrease in delivery of cholesterol to the liver decreases hepatocytecholesterol content ... leading to a compensatory increase in heptocyte LDL receptor expression ...increased clearance of circulating cholesterol Eztemibe less effective at lowering LDL than statins - combination of Ezetimibe with a statin lowers LDL by an additional 20% |
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Treatment of hypercholesterolemia
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