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79 Cards in this Set
- Front
- Back
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What is the major fat in the human diet |
triacylglycerols
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Where is most of the ingested fat digested?
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In the small intestine ingested fats are emulsified in bile salts and digested by pancreatic lipases
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What triggers the release of pancreatic lipase?
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CCK
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What is secretin? When is it released?
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secretin is an enzyme that signals the liver, pancreas, and cells of the interstitium to release bicarbonate. It is released by the small intestine in response to the entry of acidic, partially digested food arriving from the stomach.
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How does colipase aid in digestion of fatty acids?
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Co-lipase is a cofactor for lipase. It binds to both dietary fat and to the lipase relieving bile salt inhibition and allowing the TG to enter the active site of the lipase, increasing its activity
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Which of the following require bile salts for their absorbtion LCFA, SCFA, MCFA?
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Long chain fatty acids require bile salts for their absorbtion. Short and medium chain fatty acids are brought into the intestinal epithelial cells directly. They are not packaged and can be transported to the liver via portal blood, bound to serum albumin.
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What is absorbed through lymph? Portal blood?
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Chylomicrons are brought into the interstitial cells of the intestinal epithelium and travel via thoracic duct to the blood. SCFA/MCFA are secreted into the portal blood where they bind to albumin for transfer to liver.
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What is a chylomicron? What does it contain?
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A chylomicron is a lipoprotein molecule that is assembled in the intestinal cells of the intestine. They take absorbed fatty acids and 2-monoacylglycerols and reconvert them to triacylglycerol. The chylomicron contains a large amount of triglycerides and smaller amounts of cholesterol, cholesterol esters, phospholipids and fat soluble vitamins. On the surface of the chylomicron is the B48 apoprotein.
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What is an apoprotein? What apoprotein is associated with chylomicrons? VLDL?
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an apoprotein is a lipid binding protein. B48 is associated with chylomicrons. B100 is ssociated with VLDL
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Where are lipids synthesized? Where are the apoproteins assembled?
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Apoproteins are assembled in the RER while the lipids themselves are assembled in the smooth ER. The Golgi complex completes the packaging of the nascent chylomicron.
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What is transferred to nascent chylomicrons by HDL?
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The nascent chylomicrons receive apoE, apoCII from HDL. ApoE is reconized by surface receptors (particularly in the liver), while ApoCII is an activator of Lipoprotein Lipase (LPL)
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What is the function of LPL? What activates it?
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Lipoprotein Lipase digests the Triacylglycerols of the chylomicrons. LPL is attached to the basememt membranes of endothelium of vessels found in adipose muscle and mammary cells. It is produced by adipose cells, muscle cells, and cells of the lactating mammary gland. The LPL complex is activated by ApoCII. Adipose LPL is secreted in higher quantities following a meal (due to insulin stimulation).
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What is the fate of fatty acids released by LPL?
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Free fatty acids are released into the blood. They are very insoluble and therefore become bound to serum albumin. Many of the fatty acids are eventually stored as triacylglycerol in the adipocytes but they may also be oxidized for energy in muscle or other tissue depending on energy need
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What becomes of the chylomicron reminant?
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The chylomicrom remnant loses its ApoCII in the process of LPL activation. What remains is apoE which binds to receptors on hepatocytes which take it out of the blood via endocytosis for repackaging.
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What becomes of the glycerol released from the chylomicron by LPL?
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The glycerol molecule is released as LPL breaks the fatty acids from the triacylglycerol. It is often used by the liver for TAG synthesis in the fed state.
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B-48 and B-100 are similar apoproteins. What is the nature of this similarity?
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They are both produced from the same gene. B48 is found in chylomicrons and B100 is found in VLDL
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When you breakdown triacylglycerols with lipase and colipase what remains at the end?
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Free fatty acids and 2-monoacylglycerol
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What is abetalipoproteinemia?
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This is an inherited disorder that affects the ability of the body to produce apoB100 and apoB48 which are used to form VLDL and chylomicons respectively. This affects the ability to absorb, produce, and transfer lipids throughout the body. Additionally many vitamins are stored in these lipoproteins and are deficient in these patients. Patients with this condition must supplament with the fat soluble vitamins A,D,E,K as well as adhere to a very strict diet that is particularly restrictive of triglyceride intake.
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Describe the synthesis of mevalonic acid and the RLS of cholesterol synthesis
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Cholesterol synthesis begins with condensation of 2 acetyl-CoA molecules to acetoacetyl-CoA. The acetoacetyl-CoA becomes HMG-CoA which, in the RLS of cholesteol synthesis is reuced to mevalonic acid by HMG CoA reductase.
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What is an SREBP? How does it affect cholesterol syntheisis?
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SREBPs are steroid regulatory element binding proteins which affect cholesterol by dissociating the ER membrane when low intracellular cholesterol is available (no longer bound to associated SCAP protein) and activate transcription of genes that code for synthesis and uptake of cholesterol and associated cofactors required for synthesis.
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What is the effect of high or low cholesterol on SCAP /SREBP activity?
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Low cholesterol causes the SCAP/SREBP to relocate to the Golgi where the SREBP is released from SCAP to relocate to the nucleus. High cholesterol binds to the SCAP (SREBP cleavage activating protein) and prevents the SREBP/SCAP complex from leaving the ER membrane
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What is the effect of insulin on HMG CoA reductase? Glucagon?
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High insulin levels (such as those you see following a meal) activate a phosphatase which activates HMG coA reductase. When glucagon levels rise following a period of starvation an AMP activated protein kinase is activated which phosphorylates HMG coA reductase and inactivates it. Cholesterol is a very energy expensive molecule to produce. We only want to make it when energy is abundantly available.
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What is the effect of rising sterols on HMG CoA reductase?
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High sterol levels promote proteolysis an degredation of HMG CoA reductase (as synthesis of more cholesterol is not needed in the cell)
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Where does most of the biosynthesis of cholesterol occur?
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Most biosynthesis of cholestero occurs in the liver but most cells are capable of producing cholesterol.
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What is ACAT? What does it do?
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Acyl-CoA Acyl transferase. This enzyme forms cholesterol esters by transfering a fatty acid from CoA to the OH roup on carbon 3 of cholesterol. Cholesterol esters are more hydrophobic than free cholesterol. VLDL has a very large amount of colesterol esters
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What are some fates of cholesterol?
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Cholesterol is secreted from the liver as bile salts, cholseterol esters or biliary cholesterol. It is used by the tissues to form steroid hormones, and in the synthesis of vitamin D.
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What is the RLS of bile salt formation?
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Bile salts are formed in the liver and the 1st and RLS of their formation is the addition of an alpha-hydroxyl group by 7-alpha hydroxylase.
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What are the bile acids? How do they differ from bile salts? What is the pH of the intestinal lumen?
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Bile salts are the ionized form of bile acids. The interstial lumen has a pH of roughly 6
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How does the pKa of bile salts compare to the pKa of conjugated bile salts? Why does this matter?
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The pKa of bile salts are equivilant to the pH of the lumen (6). This means that about 50% of the bile acids are ionized to bile salts.
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What is the effect of bacteria on bile salts?
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Bacteria deconjugate and dehydroxylate the bile salts forming secondary bile salts.
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What is the fate of bile salts that become deconjugated and dehyroxylated
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The secondary bile salts are less readily resorbed and account for the bile salts that are excreted (<5%)
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What is enterohepatic circulation? How does this relate to bile acid turnover?
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Enterohepatic circulation is the mechanism by which 95% of bile salts are recycled from the intestinal lumen and brought back to the liver.
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What is the largest lipoprotein?
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Chylomicrons. They are also the least dense due to high Triacylglycerol content
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Where are chylomicrons produced? What do they carry? Where do they carry it?
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Chylomicrons are made within the epithelium of the small intestine and carry TAGs and other ingested fats from the intestine through the lymph to the liver.
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What are the major apolipoproteins of Chylomicrons (3) ?
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apoB48 is found on niacent chylomicrons. HDL transfers apoE and apoCII to the chylomicrons.
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What does apoCII facilitate?
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apoCII activates lipoprotien lipase, LPL hydrolyses the chylomicrons, releasing free fattyacids into target muscle cells (or acinar cells of mammary gland)
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What remains on the chylomicron reminant after binding with LPL? How does this facilitate its removal?
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The apoE molecule is still present on the chylomicron reminant. This allows the particle to be taken into the liver via endocytosis.
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Explain the circumstances that result in VLDL formation? What makes up VLDL?
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When the body has excess carbohydrates, Triglycerides are formed. These are packaged with cholesterol esters and phospholipids and apoB100 to form VLDL. Like with chylomicrons nascent VLDL accept apoCII and apoE from circulating HDL molecules.
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What is the process of maturation of a VLDL molecule?
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HDL donates apoCII and apoE to a circulating VLDL molecule. The apoCII mediates LPL activation and release of FFA and glycerol from the triglycerides stored in the molecule. What remains is a VLDL remnant.
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How does VLDL deliver tryacylglycerols to muscle, adipose and mammary tissue?
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the apoCII that the VLDL gets from HDL (it also gets apoE) binds to LPL causing hydrolysis of tryglycerides in the VLDL molecure. This releases fatty acids and glycerol for use in the tissues.
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What becomes of VLDL remnants?
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VLD remnants can be resorbed in the liver because they epress apoE. They can also have additional tryglycerides removed to become an IDL.
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What is IDL, how do you generate LDL from it?
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IDL is an intermediate density lipoprotein that is formed by removing additional triglycerides from the core of a VLDL reminant. It becomes LDL as it passes through the hepatic sinusoids and has yet even more triglycerides stripped away from it. What remains is an LDL molecule which is rich in cholesterol and cholesterol esters.
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What are LDL particles rich in?
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LDL molecules are rich in cholesterol/cholesterol esters.
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roughly 60% of LDL particles are removed by the liver? How does this happen?
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They are internalized by interaction of the LDL apoB100 molecule (that remains from when it was VLDL) with a hepatic apoB100 receptor. The remaining 40% end up in the peripheral tissues where needed for steroid hormone synthesis.
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What happens when peripheral cells are saturated and cannot take up excess LDL particles?
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When the apoB100/apoB100-R complexes become saturated the levels of LDL rise in the blood and the LDL particles can become oxidized and are prone to scavenging by macrophages near the vascular endothelium. This can cause an inflammatory reaction that can lead to atherosclerosis.
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Describe a nascent HDL particle? How does it mature?
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The HDL molecule is made in liver and intestine and is first very small, expressing many apoproteins (A1, A2, C1, C2) and very low levels of TAGs and CE's. They may also form from budding of apoproteins from chylomicrons and VLDL as LPL digestion occurs. HDLs mature by accumulating phospholipids and cholesterol from cells lining the blood vessels.
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What is reverse cholesterol transport? Why is this good?
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HDL can take cholesterol from the subintimal space and return it to the liver. ABCA1 (ATP binding cassete protien 1) uses ATP to drive cholesterol from the inner leaflet of cell membrane to the outer. Once this occurs HDL can accept it, using LCAT to trap the cholesterol as a cholesterol ester in the HDL molecule.
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what is LCAT?
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Lecithin-cholesterol acyltransferase is acquired by HDL in the circulation and catalizes the transfer of a fatty acid to an ester (forming a cholesterol ester). This ester cannot escape the HDL particle and reenter the cell.
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What is familial HDL deficiency and Tangier disease?
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These conditions involve a mutation in the ABCA 1 protein. This protein moves cholesterol from the inner cell leaflet to the outer cell leaflet. This allows HDL to remove cholesterol from the cell. This mutation will limit HDL's capacity to exist in the blood.
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How is HDL removed from the blood?
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HDL can bind the apoE receptor but most often is taken up by the SR-B1 scavenger receptor in the liver. This scavenger receptor can take the cholesterol/CE's from the HDL back into the blood and release the empty HDL back into the blood.
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What apolipoproteins does HDL transfer? To what?
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HDL transfers apoE and apoCII to chylomicrons and VLDL.
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How is cholesterol esterified by HDL?
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LCAT facilitates the formation of a cholesterol ester using Lecithin .
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What does CTEP do?
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Exchanges cholesterol esters found in HDL particles for Triglycerides found in VLDL particles
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How does HDL cycle between HDL3 and HDL2 form? Which form is atheroprotective?
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HDL3 is a mature HDL molecule. After its reverse cholesterol transport it becomoes the atheroprotective HDL2. The CTEP reaction facilitates the transfer of cholesterol to VLDL in exchange for TGs. Once the HDL has taken on enough TGs and lost enough cholesterol it is again the HDL3 molecule. Hepatic lipases remove the TGs to regenerate HDL2. The HDL3 molecule has more TGs, there fore it is a larger molecule.
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When LDL enters the cell the cholesterol esters are hydrolyzed then rapidly reesterified. What reesterifies the cholesterol?
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ACAT
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What is the effect of high intracellular cholesterol on LDL receptor expression on cell surface?
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High intracellular cholesterol will reduce expression of the LDL receptor. This process involves the SREBP system mentioned earlier in the chapter.
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What apolipoproteins are best recognized by the LDL receptor?
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ApoB100 ; ApoE
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In addition to LDL's what other lipoproteins can the LDL receptor bind, due to its high affinity for Apo100B and ApoE
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Chylomicrons, VLDL, IDL. Remember VLDL starts with B100 and never loses it as it goes to IDL, LDL. Chylomicrons and VLDLs get their apoE from HDLs
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What is familial hypercholesterolemia?
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An inherited defecit in the LDL receptor. Heterozygous carriers will have 50% expression of LDL receptor. Leading to both higher blood levels of LDL, as well as increased cholesterol production in the cells as the LDL receptor isnt able to bring in as much to downregulate. Homozygous carriers have almost no LDL-R and have serum cholesterols that are in the neighborhood of 500-800
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What is the LRP receptor? What is thought to be its main role?
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LRP is a similar structure to the LDL-r but it can recognize many different molecules, including TPA, apoE, and several inhibitors of TPA. The ability of the LRP receptor to recognize apoE allows it to remove remenants of chylomicrons and VLDL from the blood.
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What is the effect of high intracellular cholesterol on epxression of LPL receptor? What about insulin?
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Concentration of intracellular cholesterol does not affect LRP expression. Insulin increases the # of these present on the cell surface. The LRP receptor is not affected by an increase in intracelluular cholesterol. Insulin causes these receptors to increase.
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SR-B1 and SR-A1/2
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SR-B1 is a scavenger receptor used primarily for binding HDL. SR-A1/2 are scavenger receptors expressed on the surface of macrophages. These are particulary sensitive to receiving oxidized LDL. These receptors are not internalized with the LDL-o molecules and therefore can take in lots of LDL and lead to foam cell formation.
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Why can macrophages take in massive amounts of oxidized LDL particles?
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The Scavenger Receptors are not subject to downregulation in high concentrations of lipid and can thus take in oxidized LDL at all concentrations.
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What is a fatty streak?
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This is an accumulation of foam cell macrophages in the subendothelial space of a blood vessel. This is the first sign of an atherosclerotic change in a vessel.
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What causes macrophages to enter the subendothelial space of a blood vessel?
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Vascular injury due to various insults creates an inflammatory response which recruits monocytes and allows for them to accumulate and access the subendothelial space and accumulate lipids, perpetuate the inflammatory response.
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Why may a clot form at the location of an atherosclerotic lesion?
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The atherosclerotic lesion has a fibrous cap which is constantly exposed to MMPs and other collagen breakdown factors. This makes the cap unstable and prone to rupture. A rupture in the cap will result in exposure of procoagulant materials to the circulating clotting factors.
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What erodes the fibrous caps of atherosclerotic lesions and puts individuals at risk for thrombus formation?
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MMPs and sheer forces will degrade the collagen and break down the fibrin clot.
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What are the classes of steroid hormones (5)
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Glucocorticoids, mineralicorticoids, androgens, estrogens, progestins
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Why must steroid hormones bind complex with serum proteins in circulation?
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Steroid hormones are extremely hydrophobic.
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Where are androgens synthesized? In response to what?
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Androgens are synthesized in the leydig cells of the testis in response to LH.
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Where are estrogens synthesized? In response to what?
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Estrogens are synthesized in the ovarian follicle in response to FSH.
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Where are progestogens synthesized? In response to what?
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Progestins are synthesized in the corpus luteum in response to LH
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A deficiency of what enzyme is responsible for most cases of CAH?
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21 alpha hydroxylase
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Briefly describe the biosynthesis of vitamin D from cholesterol.
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Vitamin D is obtained from the diet or synthesized from a cholesterol precursor. Calcitriol (the active form of vitamin D (D3)) is produced from calcidiol
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What is a xanthelasma? Who is likely to get them?
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Xanthelasma is a lipid deposition in the eyelids seen in patients with chronic hypercholesterolemia such as that seen in familial hypercholesterolemia. These patients may also have xanthomas (arcus) arround the iris.
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What does Ezetimibe do?
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Ezetimibe blocks the absorbtion of cholesterol from the intestine. It is useful to pair this with a statin drug as endogenous cholesterol production will be induced by lower absorbtion
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How does Niacin affect cholesterol?
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Niacin is an activator of LPL. LPL reduces hepatic production of VLDL and reduces catabolism of HDL. This results in lower TG, Total, and LDL with an increase in HDL
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What is the function of the bile acid resins
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They increase fecal excretion of bile salts
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What is the function of fenofibrate?
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It antagonizes PPARa causing an increase in LPL activity, decrease in apo CIII and an increse in apo AI production |
