3 22 15 Biochemistry 401 Lecture 30 Cholesterol Transport Origin function fate of lipoprotein particles Good cholesterol vs Bad cholesterol Lipoprotein particles in disease Atherosclerosis Metabolic Disorder Lipoprotein Particles Comprised of Lipids Proteins Lipids Phospholipids Triacylglycerols Cholesterol Cholesterol esters Other lipids such as lipid soluble vitamins Protein Apolipoproteins sometimes called apoproteins polar exterior hydrophobic interior 1 3 22 15 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 Stages Nascent Chylomicron Formed but not functional intestines lymph early bloodstream Mature Chylomicron In bloodstream and functional bloodstream CII present Chylomicron Remants Leftovers return to liver bloodstream liver 2 3 22 15 Intestinal lumen apoA1 PL PL OLCE Chylomicron apoB48 OL apoA1 apoB48 apoA1 PL OLCE Chylomicron apoB48 TAG TAG CE TAG Lymph Vessel Chyomicrons leave enterocytes and enter lymph vessels Chylomicrons enter the bloodstream 3 3 22 15 CE apoCII TAG apoE HDL apoA1 Chylomicron apoB48 Bloodstream Nascent Chylomicron CE TAG apoCII apoE Chylomicron apoB48 Mature Circulating Chylomicron CE TAG apoE Chylomicron apoB48 Bloodstream apoCII Mature Circulating Chylomicron CE TAG apoE Chylomicron apoB48 Chylomicron Remnant apoE apoB48 Chylomicron TAG CE MAG FA FA apoCII apoCII Activates Lipoprotein Lipase DAG FA Proteoglycan Endothelial Cell Membrane Capillaries TAG Adipose and Muscle Cells 4 3 22 15 apoB48 TAG CE PL Chylomicron Remnant Most TAGs have been hydrolyzed Endocytosed in the liver CE TAG apoE VLDL apoB100 apoCII 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 5 3 22 15 A IDL and LDL bind LDL receptors B LDL bound receptors are endocytosed Apoprotein Binds LDL receptors 2 1 6a LDL receptors bud off into recycling vesicle 3 5 Endocytosis 4 Vesicle Acidification LDL dissociates from receptor Apoprotein B is degraded by lysosomal protease Vesicle uncoats 6b Free Cholesterol Released ACAT Esterification of cholesterol for storage S CoA Cholesterol Acyl CoA Cholesteryl Ester CoA ACAT Acyl CoA Cholesterol Acyltransferase 6 3 22 15 Catabolism of Cholesterol 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 a bile salt Cholesterol 7 oxo cholesterol e 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 syndrome 7 3 22 15 LDL receptors Required for IDL and LDL uptake Normal persons with moderate cholesterol dietary intake about 1 2 of all IDL is returned to the liver via LDL receptor mediated endocytosis Remainder becomes LDL The 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 whole IDLs 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 synthesis 8 3 22 15 Some trouble More trouble Role of LDL in Inflammation LDL Readily Enter the Artery Wall Where They May Be Modified LDL Vessel Lumen Endothelium LDL Modification of LDL components Modified LDL Aggregation Intima Modified LDL Are Proinflammatory Modified from Steinberg D et al N Engl J Med 1989 320 915 924 Atherosclerosis Is an Inflammatory Disease Vessel Lumen Monocyte Endothelium Cytokines Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Foam Cell Macrophage Intima Ross R N Engl J Med 1999 340 115 126 9 3 22 15 Progression of Atherosclerosis 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 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 stroke 10 3 22 15 HDL protective effects 1 2 3 Reverse transport of cholesterol from circulating lipoprotein particles Reverse transport of cholesterol from foam cells Degradation of oxidized lipoprotein particle constituents through an HDLassociated serum esterase Reverse Cholesterol Transport Peripheral Tissues Blood Liver Excess Cholesterol Bile Double pronged approach to Cholesterol reduction 1 Inhibition of Cholesterol Synthesis by Statins Like Lovastatin X X 2 Inhibition of Bile Associated Micelle Absorption by cationic polymers like Cholestyramine that bind and sequester Bile salts and associated micelles Micelle 11 3 22 15 Statins are Competitive Inhibitors of HMG CoA Reductase R1 R2 Statins are Competitive Inhibitors of HMG CoA Reductase R1 and R2 H R1 and R2 CH3 R1 H R2 OH R1 H R2 CH3 Compactin Simvastin Zocor Pravastatin Pravachol Lovastatin Mevacor Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes High LDL C Metabolic Syndrome Type 2 Diabetes Coronary Heart Disease
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