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RU BL 616 - Cholesterol

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11/2/20111Cholesterol Absorption, Synthesis, & Metabolism IChapter 34Nov. 4th2011Cholesterol Background• Atherosclerotic vascular disease• Stabilizes cell membrane• Precursor to bile salts and steroid hormones• Cholesterol precursors converted to ubiquinone, dolichol, & vitamine DCholesterol BackgroundSynthesis• Obtained through diet or synthesis• Synthesized in many cells, but mostly in the liver and intestine• Acetyl coenzyme A (acetyl CoA) is the precursor to cholesterol synthesis Cholesterol Background(Transport)• Chylomicrons & VLDL transport cholesterol to other cells through the bloodstream• Chylomicrons package cholesterol in intestine, while VLDL package in liver• Triacylglycerols are also transported by Chylomicrons and VLDL• HDL – reverse cholesterol transport11/2/20112Student Learning Outcomes• Describe the rate-limiting step in cholesterol synthesis and how the HMG-CoA reductase is regulated • Briefly describe the fates of cholesterol• Describe the VLDL to LDL pathway• The role of HDL– RCT, apoprotein & lipid exchange• Explain what occurs during receptor mediated endocytosis• Describe the aspects of AtherosclerosisCholesterol Synthesis• Perhydrocyclopentanophenanthrene structure consists of four fused rings• Cholesterol contains a hydroxyl group at C3, double bond between C5 & C6, eight-membered hydrocarbon chain at C17, & methyl groups at C10 & C13CholesterolPerhydrocyclopentanophenanthreneFig. 1Fig.2Cholesterol SynthesisStage I: Acetyl CoA to MevalonateA. B. C.Rate limiting stepFig.3Cholesterol SynthesisStage I: Transcription Control• Feedback regulatory system• Rate of HMG-CoA reductase mRNA synthesis controlled by sterol regulatory element binding protein (SREBP)• Once in the Golgi, SERBP is cleaved twice by S1p & S2P to release the transcription factorFig. 4A11/2/20113Cholesterol SynthesisStage I: Proteolytic Degradation of HMG-CoAReductase• When sterol present, enzyme undergoes sterol accelerated ERAD (ER associated degradation)• HMG-CoA is ubiquitinated and extracted from membrane where it is then degraded by proteosomesFig. 4BCholesterol SynthesisStage I: Regulation by Covalent Modification• Short-term regulation by phosphorylation & dephosphorylation• Adenosine monophosphate(AMP) activated kinasephosphorylates HMG-CoA• Glucagon, sterols, glucocorticoids & low ATP levels inactivate HMG-CoA• Insulin, thyroid hormone, high ATP levels activate enzymeFig. 4CCholesterol Synthesis Stage 2: Mevalonate to 2 Activated Isoprenes• Transfer 3 ATP to Mevalonatein order to activate C5 & OH-group of C3• Phosphate group at C3 & Carboxyl group of C1 leave, which produces a double bound• This allows for two active isoprenesFig.5Cholesterol Synthesis Stage 3: Condensation of Isoprenes to for Squalene• 1) Head to tail attachment of isoprenes to form Geranylpyrophosphate• 2) Head to tail condensation of Geranyl pyrophosphate and isopentenylpyrophosphate to form Farnesyl pyrophosphate• 3) Head to head fusion of two Farnesyl pyrophosphate to form squaleneFig.611/2/20114Cholesterol Synthesis Stage 4: Squalene to Four-Ring Steroid Nucleus• Squalene monooxygenase adds oxygen to form an epoxide• Unsaturated carbons (double bonds) are aligned to allow cyclization and formation of lanosterol• After many reaction get cholesterolFig. 7Fates of Cholesterol• Membranes• Cholesterol Ester• Biliary Cholesterol• Bile AcidsCholesterol Esters• Acyl-CoA:cholesterolacyl transferase (ACAT) is an ER membrane protein• ACAT transfers fatty acid of CoA to C3 hydroxyl group of cholesterol• Excess cholesterol is stored as cholesterol esters in cytosolic lipid dropletsFig. 8Bile Salts• Bile acids & salts are effective detergents• Synthesized in the liver• Stored & concentrated in the gallbladder• Discharged into gut and aides in absorption of intraluminal lipids, cholesteral, & fat soluble vitamines• Bile acid refers to the protonated form while bile salts refers to the ionized form– The pH of the intestine is 7 and the pKa of bile salts is 6, which means that 50% are protonated• These terms are sometimes used interchangeably11/2/20115Synthesis of Bile Salts• Rate-limiting step performed by the 7α-hydroxylase (CYP7A1) and is regulated by bile salt concentration• End product: Cholic acid series & Chenocholic acid series• Bile salts can be conjugated & become better detergentsFig. 9 Fig. 10Fate of Bile SaltsFig. 12Cholesterol Transport by Blood Lipoproteins• Cholesterol, cholesterol esters, triacylglycerols, & phospholipids are insoluble and must travel via lipoproteinsVLDL to LDL• The TG, free & esterified cholesterol, FA, & apoB-100 are packaged into nascent VLDL• Nascent VLDL are secreted to bloodstream and acquire apoCII & apoE from HDL to form a mature VLDL• Hepatic triglyceride lipase (HTGL) hydrolyzes additional triglycerides to produce LDL• 40% of LDL transported to extrahepatic tissues• Excess LDL is taken up by macrophagesFig. 1411/2/20116Reverse Cholesterol Transport (RCT)• HDL removes cholesterol from cells and returns it to the liver• ABC1 transport protein uses ATP hydrolysis to move cholesterol from inner leaflet to outer leaflet of membrane• HDL receives cholesterol and uses the LCAT enzyme to modify & trap the cholesterol Oram, JF & Vaughan, AM. (2000) ABCA1-mediated transport of cellular cholesterol & phospholipids to HDL apolipoproteins. Curr Opin Lipidol. June;11(3):253-60Fate of HDL• HDL can bind to specific hepatic receptors, but primary HDL clearance occurs through uptake by scavenger receptor SR-B1• Present on many cells• SR-B1 can be upregulated in cells that require more cholesterol• SR-B1 is not downregulated when cholesterol levels are high HDL binds SR-B1 receptorTransfers cholesterol & cholesterol ester to cellDepleted HDL dissociates & re-enters circulationHDL Interactions with Other Particles• HDL transfers apoE & apoCII to Chylomicrons & VLDL• HDL either transfers cholesterol & cholesterol esters directly to liver or by means of CETP to VLDL (or other TG-rich lipoproteins)• In exchange, HDL receives triacylglyceroles• Prior to CETP mature HDL particles are HDL3, post CETP they become larger and are called HDL2Fig. 16Fig. 17Receptor-Mediated Endocytosisof Lipoproteins• LDL receptor are located at coated pits, which also contain clathrin• Vesicles fuse with lysosomewhere cholesterol esters are hydrolyzed into cholesterol &


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RU BL 616 - Cholesterol

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