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Metabolism of lipids Vladimíra Kvasnicová Lipids = group of biological molecules that are insoluble in aqueous solutions and soluble in organic solvents • structural components of biological membranes • energy reserves, predominantly in the form of triacylglycerols (TAG) • excellent mechanical and thermal insulators • biologically active compounds (vitamins, hormones, bile acids, visual pigment) The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005 Structural components of lipids • alcohols glycerol (a) sfingosine (b) cholesterol (c) inositol (d) a) b) c) d) • long chain carboxylic acids (= fatty acids) The figures are adopted from http://en.wikipedia.org (April 2007) Free Fatty Acids (FFA) The figure is found at http://www.tvdsb.on.ca/saunders/courses/online/SBI3C/Cells/Lipids.htm (Jan 2007) The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005 Structure of lipids The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-2/ch11_lipid-struct.jpg (Jan 2007) The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads2/ch11_cholesterol.jpg (Jan 2007) The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005 Structure of phospholipid The figure is found at http://www.mie.utoronto.ca/labs/lcdlab/biopic/fig/3.21.jpg (Jan 2007) sphingosine ceramide = amide formed from sphingosine and fatty acid The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007) Choose compounds counting among lipids a) glycerol b) triacylglycerols c) ketone bodies d) cholesterol Choose compounds counting among lipids a) glycerol b) triacylglycerols c) ketone bodies d) cholesterol Aceton The fiugure is from the book: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2 The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990. Lipoproteins type source principal lipids important apoproteins they transport: chylomicrons intestine TAG B-48, C-II, E TAG from a diet to various tissues CHM remnants chylomicrons (CHM) cholesterol, TAG, phospholipids B-48, E remnants of chylomicrons to the liver VLDL liver TAG C-II, B-100 newly synthetized TAG to other tissues IDL VLDL cholesterol, TAG, phospholip. B-100 VLDL remnants to other tissues LDL VLDL cholesterol B-100 cholesterol to extrahepat. tissues HDL liver cholesterol, A-I, E, C-II cholesterol from phospholipids, tissues back to the store of apoprot. liver Choose correct statements about a transport of lipids in blood a) triacylglycerols are transfered mainly by chylomicrons and VLDL b) free fatty acids are bound to albumin c) cholesterol is transfered mainly by HDL and LDL d) ketone bodies do not need a transport protein Choose correct statements about a transport of lipids in blood a) triacylglycerols are transfered mainly by chylomicrons and VLDL b) free fatty acids are bound to albumin c) cholesterol is transfered mainly by HDL and LDL d) ketone bodies do not need a transport protein Releasing of free fatty acids from TAG of fatty tissue and their followed transport to target cells The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/o verheads-3/ch17_lipid-adipocytes.jpg (Jan 2007) Lipases name source location of its action function properties acid stable lipase stomach stomach hydrolysis of TAG composed of short chain fatty acids stability in low pH pancreatic lipase pancreas small intestine hydrolysis of TAG to 2 fatty acids and 2-monoacylglycerol needs pancreatic colipase lipoprotein lipase extrahepatic tissues inner surface of blood vessels hydrolysis of TAG found in VLDL and chylomicrons activated by apoC-II hormon sensitive lipase adipocytes cytoplasm of adipocytes hydrolysis of reserve triacylglycerols activated by phosphorylation acidic lipase various tissues lysosomes hydrolysis of TAG acidic pHoptimum Degradation of phospholipids (hydrolysis) The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007) Regulation of lipolysis regulatory enzyme activation hormone sensitive lipase (in adipocytes) catecholamines, glucagon (phosphorylation) lipoprotein lipase (inner surface of blood vessels) insulin apolipoprotein C-II (apoC-II) inhibition insulin prostaglandins -oxidation of fatty acids (1 cycle) dehydrogenation The figure is found at http://www.biocarta.com/pathfiles/betaoxidationPathway.asp (Jan 2007) cytoplasm Transport of fatty acids into a mitochondrion CARNITIN TRANSPORTER The figure was accepted from the book: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2 Carnitine acyltransferase regulates -oxidation regulatory enzyme carnitin palmitoyltransferase I (carnitin acyltransferase) activation inhibition malonyl-CoA (= intermediate of FA synthesis) Omega-oxidation of fatty acids (endoplasmic reticulum; minority pathway for long chain FA) The figure was found at http://www.biocarta.com/pathfiles/omegaoxidationPathway.asp (January 2007) -oxidation of fatty acids a) proceeds only in the liver b) produces NADPH+H+ c) is localized in mitochondria d) is activated by malonyl-CoA -oxidation of fatty acids a) proceeds only in the liver b) produces NADPH+H+ c) is localized in mitochondria d) is activated by malonyl-CoA Ketone bodies synthesis (= ketogenesis) • proceeds if -oxidation is • ounly in the liver: mitochondria Acetyl-CoA OH The figure is found at http://en.wikipedia.org/wiki/Image:Ketogenesis.png (Jan 2007) Ketone bodies synthesis (= ketogenesis) • proceeds if -oxidation is • ounly in the liver: mitochondria HMG-CoA is formed also in a cytoplasm during cholesterol synthesis ! Acetyl-CoA OH The figure is found at http://en.wikipedia.org/wiki/Image:Ketogenesis.png (Jan 2007) Regulation of ketogenesis regulatory enzyme activation inhibition hormon sensitive ratio ratio lipase glucagon / insulin insulin / glucagon (lipolysis in fatty catecholamines tissue) carnitin malonyl-Co A acyltransferase I ratio (transfer of fatty insulin / glucagon acids into mitochondria) Ketone bodies degradation (oxidation) proceeds during starvation in extrahepatic tissues as an alternative energy source (in a brain as well) Citrate cycle The figure is found at http://www.richmond.edu/~jbell2/19F18.JPG (Jan 2007) Ketone bodies a) are synthesized from acetyl-CoA b) are produced by muscle tissue as a consequence of increased fatty acid oxidation c) serve as an energy substrate for erythrocytes d) can be excreted with urine Ketone bodies a) are synthesized from acetyl-CoA b) are produced by muscle tissue as a consequence of increased fatty acid oxidation c) serve as an energy substrate for erythrocytes d) can be excreted with urine Fatty acid synthesis (1 cycle) The figure is found at http://herkules.oulu.fi/isbn9514270312/html/graphic22.png (Jan 2007) „activated carbon“ Transport of acetyl-CoA from a mitochondrion to the cytoplasm FA synthesis NADPH from pentose cycle The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#synthesis (Jan 2007) Regulation of fatty acid synthesis regulatory enzyme acetyl CoA carboxylase (key enzyme) fatty acid synthase activation inhibition citrate insulin low-fat, energy rich high saccharide diet (induction) acyl-CoA (C16- C18) glucagon (phosphorylation, repression) lipid rich diet, starvation (repression) phosphorylated saccharides low-fat, energy rich high saccharide diet (induction) glucagon (phosphorylation, repression) lipid rich diet, starvation (repression) The pathway of synthesis of fatty acids a) produces NADPH+H+ b) starts by carboxylation of acetyl-CoA: malonyl-CoA is formed c) is localized in mitochondria d) includes reduction steps The pathway of synthesis of fatty acids a) produces NADPH+H+ b) starts by carboxylation of acetyl-CoA: malonyl-CoA is formed c) is localized in mitochondria d) includes reduction steps Comparision of fatty acid synthesis and degradation synthesis -oxidation active under the conditions saccharide rich diet starvation ratio insulin/glucagon high low the most active tissue liver muscles, liver cellular location cytoplasm mitochondria transport through a mitochondrial membrane citrate (= acetyl to cytoplasm) acyl-carnitin (= acyl to matrix) acyl is bound to ACP-domain, CoA CoA coenzymes of oxidoreductases NADPH NAD+, FAD+ C2 donor/product malonyl-CoA = donor of acetyl acetyl-CoA = product activator / inhibitor citrate / acyl-CoA -/ malonyl-CoA product palmitic acid acetyl-CoA Biosynthesis of triacylglycerols The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007) Regulation of TAG metabolism regulatory enzyme activation phosphatidic acid phosphatase steroid hormones (induction) lipoprotein lipase (important for storage of TAG in a fatty tissue) insulin apolipoprotein C-II inhibition Biosynthesis of cholesterol regulatory enzyme The figure is found at http://web.indstate.edu/thcme/mwking/cholesterol.html (Jan 2007) cholesterol synthesis ketone bodies The figure is found at http://amiga1.med.miami.edu/Medical/Ahmad/Figures/Lecture9/Slide23.jpg (Jan 2007) Synthesis of cholesterol consumes ATP activated isoprene The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007) activated isoprene: two frorms The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007) The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007) Regulation of cholesterol synthesis regulatory enzyme HMG-CoA reductase activation insulin, thyroxine (induction) inhibition cholesterol glucagon (repression) oxosterols (repression) Cholesterol a) is synthesized in mitochondria b) synthesis includes the same intermediate as ketogenesis: acetone c) can be broken down to acetyl-CoA d) is synthesized if the ratio insulin/glucagon is low Cholesterol a) is synthesized in mitochondria b) synthesis includes the same intermediate as ketogenesis: acetone c) can be broken down to acetyl-CoA d) is synthesized if the ratio insulin/glucagon is low