Lipid Circulation PDF

Circulació Intracel.lular i Extracel.lular de Lípids Tema 4  Lipoproteïnes Cholesterol is in blood at a concentration 106 x its solubility in water. How is this accomplished?  Lipoproteïnes Lipoprotein Densit...

Circulació Intracel.lular i Extracel.lular de Lípids Tema 4  Lipoproteïnes Cholesterol is in blood at a concentration 106 x its solubility in water. How is this accomplished?  Lipoproteïnes Lipoprotein Density Diameter Protein % Phospholi Triacylglycerol class (g/mL) (nm) of dry wt pid % % of dry wt HDL 1.063-1.21 5 – 15 33 29 8 LDL 1.019 – 18 – 28 25 21 4 1.063 IDL 1.006-1.019 25 - 50 18 22 31 VLDL 0.95 – 1.006 30 - 80 10 18 50 chylomicrons < 0.95 100 - 500 1-2 7 84 Lipoproteïnes Lipoproteïnes Lípids transportats per Lipoproteïnes Lipoproteïnes Metabolisme de les lipoproteïnes Lipoproteïnes: Quilomicrons Lipoproteïnes: Quilomicrons Lipoprotein lipasa  Lipoproteïnes ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of TG Lipoproteïnes: VLDL Lipoproteïnes: VLDL Lipoproteïnes Lipoproteïnes: LDL  VLDL Remnant Uptake The remnant particle (IDL), if it contains apoE, can be taken up by the apoE/remanant receptor Lipoproteïnes: LDL  Lipoproteïnes: LDL LDL is removed by apoB100 receptors which are mainly expressed in the liver Hepatic Lipase Cholesteryl ester transfer protein Representation of the LDL receptor (839 aa) extracellular domain is responsible for apo-B- 100/apo-E binding intracellular domain is responsible for clustering of LDL receptors into coated pit region of plasma membrane  Lipoproteïnes: receptor LDL Brown and Goldstein Nobel in Medicine, 1985 Michael Brown Joseph Goldstein Lipoproteïnes: HDL Surface Monolayer Phospholipids (25%) Free Cholesterol (7%) Protein (45%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (18%) Lipoproteïnes: HDL  Lipoproteínas: HDL Particle Shape Apolipoprotein Composition Discoidal Spherical A-I HDL A-I/A-II A-II HDL HDL Particle Size Lipid Composition TG, CE, and PL HDL2b HDL2a HDL3a HDL3b HDL3c Rye KA et al. Atherosclerosis 1999;145:227-238.  HDL Maturation HDL is secreted in a discoidal form from the liver and gut. As it acquires cholesterol from tissues in the circulation, it matures into a spherical form through the action of lecithin:cholesterol acyl transferase Transport del colesterol  ABCA1 SR-BI Hiperlipidaemies  HDL is Protective 120 110 186 events in 4,407 per 1,000 (in 6 years) 100 men (aged 40–65 y) 80 Incidence 60 40 30 21 20 0 < 35 35–55 > 55 HDL-C (mg/dL) Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993 The atherogenic lipoprotein phenotype Digestió del colesterol  Funcions del colesterol Membrane component Steroid synthesis Bile acid/salt precursor Vitamin D precursor Molècula de colesterol Síntesi de colesterol Síntesi de colesterol Síntesi de colesterol HMG-CoA reductasa Fosforilació de l’HMG-CoA reductasa  Regulació de la Síntesi de colesterol Transcriptional regulation – SREBP-2 – Responds to cellular levels of sterols  Regulació de la Síntesi de colesterol SREBP cleavage activating protein Regulació de la Síntesi de colesterol Site 1 and site 2 protease - Model for conformational change in SCAP [sterol regulatory element-binding protein (SREBP) cleavage-activating protein]. (a) In membranes from sterol-deprived cells, trypsin cleaves SCAP on its N-terminal side at R496. Two point-mutations, Y298C and D443N, render the sterol-sensing domain of SCAP resistant to the cholesterol-induced conformational change. (b) Addition of cholesterol created a new trypsin cleavage site at R503 and R505, whereas the trypsin cleavage site on the C-terminal side of SCAP occurs within the same cluster of arginines (R747–R750) both in the absence and presence of cholesterol. The conformational change in SCAP might be produced by intramembranous cholesterol interaction with the transmembrane helices of the sterol-sensing domain. Reproduced, with permission, from Ref.  Regulació de la Síntesi de colesterol HMG-CoA reductase, which catalyzes the committed reaction in cholesterol biosynthesis is a primary target for regulation dietary cholesterol suppresses the endogenous synthesis of cholesterol at both transcriptional and translational levels HMG-CoA reductase is also regulated hormonally, by insulin and glucagon at the transcriptional level in vertebrates, the rate of endogenous cholesterol synthesis is controlled by coordination with the rate of cholesterol use by cells and by dietary intake Inhibidors de l’HMG-CoA reductasa