Diseases of Lipid Metabolism PDF

Diseases of Lipid Metabolism Topics: 1. Lipids (review and analytical methods) 2. Energy Balance and Obesity 3. Adipose Tissue and Adipogenesis 4. Triacylglycerol Synthesis 5. Obesity Therapies Dr. Scot Stone 6. Lipolysis Dept of Biochemistry, Microb...

Diseases of Lipid Metabolism Topics: 1. Lipids (review and analytical methods) 2. Energy Balance and Obesity 3. Adipose Tissue and Adipogenesis 4. Triacylglycerol Synthesis 5. Obesity Therapies Dr. Scot Stone 6. Lipolysis Dept of Biochemistry, Microbiology and Immunology 7. Cholesterol and Atherosclerosis [email protected] 8. Lipoprotein Assembly 9. Hyperlipidemia 10. Phosphatidylserine and Blood Coagulation 11. Cardiolipin and Barth Syndrome  What are Lipids? Lipids are non-polar molecules that do not dissolve in water Lipids are hydrophobic Long chains of hydrocarbons high number of C-C and C-H bonds → don’t like to interact with water https://www.vinmec.com/en/gastroenterology- hepatobiliary/health-news/digestion-and-absorption-of-lipids/  Lipids – diverse group of molecules Fatty Acids Glycerolipids Lipids Saturated Unsaturated Triacylglycerol Phospholipids Non-glycerolipids Lipid Complexes Lipids + Sphingolipids Waxes Sterols Proteins Lipoproteins Lipid Droplets (Extracellular) (Intracellular) Cholesterol  Polar vs Non-polar lipids Phospholipids are polar lipids: have both a hydrophilic (water-attracting) "head" and a hydrophobic (water-repelling) "tail.“ can interact with both water and lipids FA, TG, CE are non-polar lipids: are hydrophobic (do not interact well with water) due to the lack of polar regions. consist mainly of long hydrocarbon chains  Fatty acids Fatty acids in humans contain between 4 - 22 carbons Many double bonds, low melting point, liquid at room temp No double bonds, higher melting point, solid at room temp Carboxyl group Hydrocarbon chain Components of: Phospholipids → membrane structure, cell signalling Triacylglycerol → stored energy Source of ATP Cholesterol + Fatty Acid Cholesterol ester Proteins are attached to certain fatty acids (14:0, 16:0) → membrane attachment https://socratic.org/questions/how-do-london-dispersion-forces-relate-to-the-boiling-point-of-a-compound https://microbiologynote.com/fatty-acid-definition-structure-types-functions/  Olive Oil Beef Lard Lots of saturated fats Lots of polyunsaturated fats  Fatty acids – many different types Saturated fatty acids Lauric acid Dodecanoic acid 12:0 Myristic acid Tetradecanoic acid 14:0 Number of Location of Palmitic acid Hexadecanoic acid 16:0 Stearic acid Octadecanoic acid 18:0 carbons double bonds Arachidic acid Icosanoic acid 20:0 Behenic acid Docosanoic acid 22:0 18:2 9,12 Lignoceric acid Tetracosanoic acid 24:0 Monounsaturated fatty acids Caproleic acid dec-9-enoic acid 10:1 9 Lauroleic acid dodec-9-enoic acid 12:1 9 Myristoleic acid tetradec-9-enoic acid 14:1 9 Number of Palmitoleic acid hexadec-9-enoic acid 16:1 9 double bonds Oleic acid octadec-9-enoic acid 18:1 9 Gadoleic acid icos-9-enoic acid 20:1 9 Erucic acid docos-13-enoic acid 22:1 13 Nervonic acid tetracos-15-enoic acid 24:1 15 Polyunsaturated fatty acids Linoleic acid (LA) octadeca-9,12-dienoic acid 18:2 9,12 -Linolenic acid (ALA) octadeca-9,12,15-trienoic acid 18:3 9,12,15 -Linolenic acid (GLA) octadeca-6,9,12-trienoic acid 18:3 6,9,12 Stearidonic acid (octadeca-6,9,12,15-tetraenoic acid 18:4 9 6,9,12,15 Eicosatrienoic acid icosa-5,8,11-trienoic acid 20:3 5,8,11 Dihomo-γ-linolenic acid (DGLA) icosa-8,11,14-trienoic acid 20:3 8,11,14 Arachidonic acid icosa-5,8,11,14-tetraenoic acid 20:4 5,8,11,14 Eicosapentaenoic acid (EPA) icosa-5,8,11,14,17-pentaenoic acid 20:5 5,8,11,14,17 Docosapentaenoic acid (DPA) docosa-7,10,13,16,19-pentaenoic acid 22:5 7,10,13,16,19 Docosahexaenoic acid (DHA) docosa-4,7,10,13,16,19-hexaenoic acid 22:6 4,7,10,13,16,19  Fatty Acids (Palmitate) are synthesised from acetyl CoA Sources of Fatty acids: Diet Synthesis Fatty Acid Synthase 8 acetyl CoA + 7 ATP + 14 NADPH 1 palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O How do we make fatty acids longer? Add double bonds?  Production of ATP from Fatty Acid Oxidation (β-oxidation) Products of FA oxidation: Acetyl CoA, FADH2, NADH  Phospholipids A diverse group of related molecules Polar head group Polar Structural Group Phosphate Glycerol Fatty Acid Fatty Acid Lipid bilayer/biological membrane Non-polar tails Fatty acid composition of phospholipids regulates membrane fluidity: rigid enough to be a barrier Flexible enough to allow transport of proteins, lipids, other molecules https://socratic.org/questions/what-are-the-main-functions-of-the- cell-membrane Common Phospholipids: Phosphatidyl-headgroup R1 and R2 = Fatty acids Structural/ protein tether Structural Signaling/protein tether Phosphatidylethanolamine Charge = 0 Phosphatidylcholine Charge = 0 Signaling/ Apoptosis/ protein tether Blood clotting Phosphatidylserine Charge = -1 Apoptosis Phosphatidylinositol Blood clotting Charge = -1  Phosphatidylethanolamine,phosphatidylinositol and glycosylphosphatidylinositol (GPI) anchors Glycosylphosphatidylinositol (GPI) anchor functions to tether proteins to outside of cell membrane 150 human proteins are GPI-anchored proteins Phosphatidylinositol https://www.uptodate.com/contents/image?imageKey=HEME%2F96559 Different cellular membranes have different phospholipid compositions https://www.genome.gov/genetics-glossary/Organelle Different cellular membranes have different phospholipid compositions Phospholipid composition of mammalian cell membranes Percentage of total phospholipids Endoplasmic Mitochondria Plasma Membrane Reticulum Inner Membrane Outer Membrane Sphingomyelin Cardiolipin (Diphosphatidylglycerol) Phosphatidyl Glycerol Phosphatidyl  Lipid Asymmetry of the plasma membrane Cellular membranes contain different types/proportions of lipids Each membrane layer has distinct types of lipids https://socratic.org/questions/what-are-the-main-functions-of-the- cell-membrane Fadeel and Xue, 2009 (CRBMB)  Lipid asymmetry of the plasma membrane regulates signals Phosphatidylserine Substrate + + -- + -- + Active enzyme + Inactive enzyme - Product + + Exposure of PS to outer creates regions that are negatively charged than can interact with regions of proteins that are positively charged Lipid Asymmetry of the plasma membrane allows for membrane curvature Each phospholipid has a unique shape (headgroup and fatty acids) Phosphatidylcholine Phosphatidylethanolamine Cylindrical Flat sheets Conical Curvature A mixture of conical and cylindrical lipids allows for necessary curvature and flexibility of a membrane  Triacylglycerols (TG, TAG) – store fatty acids, a major source of energy Fatty acids are connected to glycerol by an ester bond sn1 sn2 sn3 Each carbon of the glycerol backbone has a designation → sn1, sn2, sn3 sn – stereospecific numbering Why don’t we just store fatty acids instead of TG? Fatty acids are toxic to cells at high concentrations abnormal cellular signaling dissolve cellular membranes TG are chemically inert  TG typically have a mixed FA composition Fatty Acids in TG Adipose Tissue 14:0 16:0 16:1 18:0 18:1 18:2 18:3 20:1 sn-1 sn-2 sn-3 Rule of thumb for fatty acids: C1: saturated > unsaturated C2 and C3: saturated < unsaturated  TG typically have a mixed FA composition Fatty Acids in TG 4:0 6:0 8:0 10:0 12:0 14:0 16:0 16:1 18:0 18:1 18:2 18:3 20:1 20:5 22:1 22:5 22:6 Adipose Milk Fish Oil Milk: enriched in short chain (C4-14) saturated fatty acids (65%) promote growth of beneficial gut bacteria immune function Fish Oil (Herring): enriched in long chain (>20C) polyunsaturated fatty acids (56%) lower blood cholesterol and triacylglycerols reduce chance of atherosclerosis reduce blood pressure  Kennedy Pathway of Lipid synthesis Dr. Eugene Kennedy (1919–2011)  Kennedy Pathway of Lipid synthesis Phosphatidic acid Phosphatidylcholine 1,2 diacylglycerol Phosphatidylserine Phosphatidylethanolamine Triacylglycerol  Adipose Tissue: major site of TG storage Adipose Tissue Adipocyte TG https://study.com/learn/lesson/adipose-tissue-function-anatomy.html Adipose tissue has very high capacity for TG storage Adipocyte → almost entire cell volume is filled with TG Also lots of TG in liver, small intestine, mammary gland  Catabolism of Stored FAT in Adipose Tissue -  Energy (low blood [glucose]) Lipolysis glucagon, epinephrine Adipose Tissue Lipases β-oxidation Muscle CO2 + ATP Cholesterol https://www.cartoonstock.com  Functions of Cholesterol Bile Acids (Storage form of cholesterol) (Cholesterol ester) Storage form of cholesterol Membrane fluidity R = fatty acid ~30-50% of the lipids in the plasma membrane are OH cholesterol In plasma membrane: [outer leaflet] = [inner leaflet] No asymmetry O https://socratic.org/questions/what-is-the-function- Steroid hormones of-cholesterol-molecules-in-the-cell-membrane  High levels of cholesterol contribute to atherosclerosis BSIP VEM/SCIENCE PHOTO LIBRARY https://my.clevelandclinic.org/health/diseases/16753-atherosclerosis-arterial-disease  Sources of Cholesterol Diet or synthesis in liver (from acetyl CoA) 3 Acetyl CoA Regulation of cholesterol synthesis Balance between synthesis and dietary uptake feedback inhibition by INTRACELLULAR cholesterol β-Hydroxy-β- methylglutaryl CoA (HMG CoA) HMG CoA Reductase Michael S. Brown Joseph L. Goldstein Nobel Prize in Physiology or Medicine 1985 Mevalonate Cholesterol  Lipid Transport between tissues Cholesterol and triacylglycerol are transported by lipoproteins Lipoproteins (4 types): complexes of lipids and proteins transport triacylglycerols (TG) and cholesterol in blood chylomicrons, VLDL, LDL and HDL (density and size) Chylomicrons and VLDL → transport TG LDL and HDL→ transport Cholesterol and triacylglycerol Circulating Lipids - lipoproteins Chylomicron:  lipid:protein → larger, but lighter HDL:  lipid:protein → smaller, but heavier Proteins bound to lipoproteins are “apolipoproteins” Good vs Bad Cholesterol LDL (low-density lipoprotein) = bad cholesterol Most of your body’s cholesterol High levels of LDL cholesterol raise your risk for heart disease and stroke. HDL (high-density lipoprotein) = good cholesterol Carries cholesterol from tissues to the liver Excreted from the body in bile High levels of HDL cholesterol lowers your risk for heart disease and stroke. https://nationworldnews.com/why-shouldnt-we-talk-about-good-and- bad-cholesterol-anymore/ Lipid Transport