3/22/15&1&Biochemistry401Lecture 30 Cholesterol Transport:Origin, function, fate of lipoprotein particles“Good cholesterol” vs. “Bad cholesterol” Lipoprotein particles in disease:AtherosclerosisMetabolic DisorderLipoprotein Particles Comprised of: Lipids Proteins Lipids: Phospholipids Triacylglycerols Cholesterol Cholesterol esters Other lipids (such as lipid soluble vitamins) polar exterior hydrophobic interior Protein: Apolipoproteins (sometimes called apoproteins)3/22/15&2&Apolipoprotein B-48 is only made in the small intestine Deamination of Cytidine to Uridine introduces a stop codon. This deaminase is only in small intestine. Chylomicron Three StagesNascent Chylomicron: Formed but not functional intestines, lymph, early bloodstreamMature Chylomicron: In bloodstream and functional bloodstream, CII presentChylomicron Remants: Leftovers return to liver bloodstream, liver3/22/15&3&TAG!CE!Chylomicron!apoB48apoA1PL!OL!TAG!CE!PL!OL! apoA1!apoB48!TAG!CE!Chylomicron!apoB48apoA1PL!OL!Intestinal lumen!Lymph Vessel!Chyomicrons leave enterocytes and enter lymph vessels…! !Chylomicrons enter the bloodstream!!!3/22/15&4&HDL!TAG!CE!Chylomicron!apoB48apoA1Nascent Chylomicron !Bloodstream !apoEapoCIIMature Circulating Chylomicron!TAG!CE!Chylomicron!apoB48apoCIIapoEMature Circulating Chylomicron!Bloodstream !TAG!CE!Chylomicron!apoB48apoEapoCIIChylomicron Remnant!TAG!CE!Chylomicron!apoB48apoEProteoglycan!TAG!CE!Chylomicron!apoCIIapoB48apoEDAG!TAG!MAG!TAG!FA!FA!apoCII Activates !Lipoprotein Lipase!Endothelial Cell Membrane!Capillaries!Adipose !and!Muscle !Cells!FA!FA!3/22/15&5&TAG!CE!PL!apoB48Chylomicron Remnant!Most TAGs have been hydrolyzed !Endocytosed in the liver !VLDL formed in the liver!Take up E and CII from HDL and bind to endothelial cells - TAGS are hydrolyzed and released. VLDLs become smaller as this happens - First to IDL, and then LDL!TAG!CE!VLDL!apoB100apoEapoCII3/22/15&6&(A) IDL and LDL bind LDL receptors (B) LDL-bound receptors are endocytosed Apoprotein B is degraded by lysosomal protease Vesicle uncoats Vesicle Acidification LDL dissociates from receptor ACAT: Esterification of cholesterol for storage Free Cholesterol Released LDL receptors bud off into recycling vesicle 1 2 3 4 5 6a 6b Apoprotein Binds LDL receptors Endocytosis ACAT!Cholesterol + Acyl CoA ! Cholesteryl Ester + CoA !S-CoA!Acyl-CoA Cholesterol Acyltransferase!3/22/15&7&Cholesterol is scavenged from the tissues Converted to bile salts, amphipathic derivatives of cholesterol • Synthesized in the liver • Stored in the gall bladder • Released into the small intestine 95% of the bile salts are taken up again by the small intestines along with emulsified TAGs and other dietary lipids. 5% are excreted in the feces. Catabolism of Cholesterol? a bile salt 7-oxo cholesterol !Cholesterol !Cytochrome p450 this is a heme containing monooxygenase enzyme that is used to oxygenate sterols to produce bile salts and sterols!Also used in detoxification. !The good the bad and the ugly: “good cholesterol” “bad cholesterol” The role of lipoprotein particles in coronary heart disease and metabolic syndrome3/22/15&8&LDL receptors: Required for IDL and LDL uptakeNormal persons with moderate cholesterol dietary intake:• about 1/2 of all IDL is returned to the liver via LDL receptor-mediated endocytosis• Remainder becomes LDLThe amount of circulating LDL depends in large part on how well IDL can be removed from circulation:• The number of LDL receptors on the cell surface relative to the amount of circulating IDL particles.• The proper functioning of LDL receptors themselves and receptor-mediated endocytosis as a wholeIDLs can’t effectively get into the liver cell Remain circulating, to become LDLs !Hypercholesterolemia Too much cholesterol in the blood LDL is left circulating because it is not internalized at sufficient rate A) Familial hypercholesterolemia (FH) - • FH/FH: Serum Cholesterol is 3 to 5 times normal levels beginning in childhood. • FH/+: Serum Cholesterol is about twice normal levels by middle age. - Not enough LDL receptors on the cell surface - Normal amount, but poorly functioning, LDL receptors B) Long-term ingestion of dietary cholesterol far exceeds requirement • LDL receptor synthesis is regulated by cholesterol levels - High cholesterol ! Decrease in LDL receptor synthesis - Low cholesterol ! Increase in LDL receptor synthesis3/22/15&9&Some trouble! More trouble!Role of LDL in Inflammation Modified from Steinberg D, et al. N Engl J Med. 1989;320:915-924. Endothelium Vessel Lumen LDL LDL Readily Enter the Artery Wall Where They May Be Modified LDL Intima Modified LDL Modified LDL Are Proinflammatory Modification of LDL components Aggregation Atherosclerosis Is an Inflammatory Disease Ross R. N Engl J Med. 1999;340:115-126. Endothelium Vessel Lumen Intima Foam Cell Monocyte Cytokines Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Macrophage3/22/15&10&Lipoprotein particles are transported to the endothelial tissue. Lipoprotein particles infiltrate into the tissue of the blood vessel. Lipoprotein particles are modified through oxidative damage. This causes inflammation to occur. Monocytes adhere to the blood vessel. Monocytes migrate into the blood vessel tissue. Monocytes differentiate to become macrophages. Macrophages form foam cells through phagocytosis of LDL particles. Progression of Atherosclerosis Fatty Streaks Plaques, Infarcts Build up of foam cells and scarring: a fatty streak Fatty streaks can become plaques Plaques can rupture and cause blood clots to form Thrombosis can cause infarction - heart attack or stroke3/22/15&11&HDL protective effects1) Reverse transport of cholesterol from circulating lipoprotein particles2) Reverse transport of cholesterol from foam cells3) Degradation of oxidized lipoprotein particle constituents through an HDL-associated serum esteraseReverse Cholesterol Transport Blood Peripheral Tissues Liver Bile Excess Cholesterol Micelle 2) Inhibition of Bile Associated Micelle Absorption by cationic polymers like Cholestyramine that bind and sequester Bile salts and associated micelles X 1) Inhibition of Cholesterol Synthesis by Statins Like Lovastatin X Double-pronged approach to Cholesterol reduction3/22/15&12&R1 R2 Statins are Competitive Inhibitors of HMG-CoA Reductase Statins are Competitive Inhibitors of HMG-CoA Reductase R1 and
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