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Lipid Metabolism Sara M.Abuel Gassim January 2010 INTRODUCTION •Lipids, such as cholesterol and triglycerides, are insoluble in plasma and circulating lipid is carried in lipoproteins that transport the lipid to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation. •The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, phospholipids, and protein. • The protein components of the lipoprotein are known as apolipoproteins (apo) or apoproteins. •The different apolipoproteins serve as cofactors for enzymes and ligands for receptors. Classification of lipoproteins There are five major lipoproteins, each of which has a different function. •Chylomicrons are very large particles that carry dietary lipid. They are associated with a variety of apolipoproteins. •Very low density lipoprotein — (VLDL) carries endogenous triglycerides and to a lesser degree cholesterol. •Intermediate density lipoprotein. •Low density lipoprotein. •High density lipoprotein. 3 Lipids •Are groups of heterogeneous compounds characterized by their solubility properties. •They are insoluble in water, but are soluble in organic solvents such as ether chloroform, and benzene. Classification of lipids 1. Simple Lipids a. Fats b. Waxes 2. Complex Lipids a. Glycerophospholipids b. Sphingolipids c. Sterols 3. Derived lipids or lipids with specific biological activity Simple lipids They are esters of fatty acids with alcohols. Two types: •Fats, oils, acylglycerols, neutral lipids; these are esters of fatty acids with glycerol eg. Triacyl glycerol •Waxes are esters of fatty acids with long chain monohydric alcohol Fatty Acids CH3(CH2)nCH2CO 2H O O CH3(CH2)nCH2C-OH H-O-R CH3(CH2)nCH2C-OH O O CH3(CH2)nCH2C-O-R Ester H-S-R CH3(CH2)nCH2C-S-R Thioester Complex lipids • glycerophospholipids • sphingolipids A- phosphosphingolipids B- glycosphingolipids •Sterols (cholesterol) Fats or oils or Acylglycerols • Esters of fatty acids with glycerol; mono-di- or triacylglycerol (TAG). • The main storage form of fuel in animals is TAG. • It is stored in adipose tissues. • It is hydrophobic molecule, therefore it is transported in blood by the lipoprotein particles mainly chylomicrons and very low density lipoprotein (VLDL). 10 •Transported in blood bound to albumin •Can be oxidized by various tissues (β-oxidation) to generate metabolic energy. •Some are not synthesized in animal body, thus are dietary essential e.g. (linoleic, and linolenic acids) Dietary Fatty Acids • Triacylglycerols, phospholipids, sterol esters • Principal sources: dairy products, meats Digestion of Dietary Triacylglycerols • Occurs in duodenum • Facilitated by • Bile salts (emulsification) • Alkaline medium (pancreatic juice) Pancreatic lipases OH OH TAG MAG Intestinal lipases Glycerol + Fatty Acids Epithelial Cell (Intestinal Wall) MAG Glycerol Fatty Acids Intestinal lumen Lipoprotein TAG Lymphatics Blood (bound to albumin) Chylomicrons Adipose Tissue And Muscle Adipocytes Fat Storage • Mainly as triacylglycerols (triglycerides) in adipose cells • Constitute 84% of stored energy • Protein - 15% • Carbohydrate (glucose or glycogen) - <1% Processing of Lipid Reserves: Overview 1. Lipid Mobilization: In adipose tissue TAGs hydrolyzed to fatty acids plus glycerol 2. Transport of Fatty Acids in Blood To Tissues 3. Activation of Fatty Acids as CoA Ester 4. Transport into Mitochondria 5. Metabolism to Acetyl CoA Release of Fatty Acids from Triacylglycerols O CH 2OC-R1 O CH 2OH Lipases CHOC-R 2 CHOH O CH 2OC-R3 CH 2OH Triacylglycerol Glycerol + O O O HOC-R 1 HOC-R 2 HOC-R 3 Lipolysis •Lipolysis is the hydrolysis of lipids . Metabolically it is the breakdown of triglycerides into free fatty acids within cells. •When fats are broken down for energy the process is known as beta oxidation. •Ketones are produced, and are found in large quantities in ketosis. Lipolysis Hormone (Adrenalin, Glucagon, ACTH) Receptor (7TM) Activates ATP Insulin blocks this step Adenylyl Cyclase c-AMP Activates lipase Triacylglycerols Glycerol + Fatty acids Adipose Cell Blood Adenylyl cyclase ATP Phosphodiesterase c-AMP AMP Enhanced by glucagon Enhanced by insulin Inactive Kinase Activated Kinase P Inactive Lipase Activated Lipase Phosphatase Insulin favors formation of the inactive lipase Triacylglycerol (Hormone-sensitive Lipase) Glycerol + Fatty Acids Acylglycerol Lipases Diacylglycerol (DAG) Triacylglycerol Lipase OH Triacylglycerol (TAG) OH OH OH Glycerol Monoacylglycerol Lipase Diacylglycerol Lipase OH OH Monoacylglycerol (MAG) Fate of Glycerol Pyruvate In Liver: OH OH OH Glycolysis Dihydroxyacetone Phosphate Gluconeogenesis Glycerol Glucose Beta Oxidation • Cleavage of fatty acids to acetate in tissues • Occurs in mitochondria [O] [O] [O] [O] [O] [O] [O] [O] CO2 H 9 CH3COSCoA Steps in Beta Oxidation • Fatty Acid Activation by Esterification with CoASH • Membrane Transport of Fatty Acyl CoA Esters • Carbon Backbone Reaction Sequence • Dehydrogenation • Hydration • Dehydrogenation • Carbon-Carbon Cleavage (Thiolase Reaction) Beta Oxidation Reaction Sequence Acyl CoA H Dehydrogenase R-CH2 -C-C-COSCoA R-CH2 -C=C-COSCoA H H H H FAD FADH2 L--Hydroxyacyl CoA Dehydrogenase -Ketoacyl CoA H NADH + H+ CoASH trans-2 -enoyl CoA H2 O Enoyl CoA Hydratase H H R-CH2 -C-C-COSCoA R-CH2 -C-C-COSCoA OH H NAD+ HO H L--Hydroxyacyl CoA Thiolase (-ketothiolase) R-CH2 -C-SCoA O + Occurs in Mitochondria CH 3 -C-SCoA O Repeat Sequence Ketone Bodies As Energy Sources In liver -Hydroxybutyrate Acetoacetate Acetoacetate is major energy source in cardiac muscle and renal cortex; also in brain in starvation and diabetes Succinyl CoA -Ketoacyl CoA transferase Not found in liver Thiolase 2 Acetyl CoA Combines with oxaloacetate TCA Cycle Acetoacetyl CoA Succinate Fatty Acid Synthesis vs. Degradation Synthesis Degradation Intermediates Linked to SH in Proteins (Acyl Carrier Proteins) Linked to CoASH Site Cytosol Mitochondria Enzymes Components of Single Peptide Redox Coenzymes NADP+ / NADPH Separate Polypeptides NAD+ / NADH Fatty Acid Biosynthesis • Occurs in cytosol • Starts with acetyl CoA • Problem: » Most acetyl CoA produced in mitochondria » Acetyl CoA unable to traverse mitochondrial membrane. Citrate As Carrier of Acetate Groups Cytosol Glucose Mitochondria Pyruvate Pyruvate Acetyl CoA Pyruvate Dehydrogenase Malic enzyme Malate Malate dehydrogenase Citrate Acetyl CoA Oxaloacetate Oxaloacetate ATP-Citrate Lyase Note: Acetyl CoA cannot be converted to glucose Citrate Mitochondrial membrane Respiratory Distress Syndrome •Most frequently seen in premature infants •Also called hyaline membrane disease •Failure to produce sufficient dipalmitoyl phosphatidylcholine, which normally is found in the extracellular fluid surrounding alveoli; decreases surface tension of fluid to prevent lung collapse. Tay-Sachs Disease •GM2 (a ganglioside): •Ceramide - O - Glucose - Galactose - N-Acetylgalactose •Hexoseaminidase A catalyzes cleavage of this glycoside linkage •Autosomal recessive disorder characterized by deficiency of hexoseaminidase A; accumulation of gangliosides in brain •Most prevalent in Jews from Eastern Europe Metabolite Regulation of Fatty Acid Synthesis and Breakdown Glucose Citrate Stimulates Blocks Pyruvate Acetyl CoA Malonyl CoA Inhibits Palmitoyl CoA Beta Oxidation Hormonal Regulation of Fatty Acid Synthesis and Breakdown Phosphodiesterase Adenylyl cyclase ATP cAMP Stimulates Glucagon and epinephrine Inhibition of fatty acid synthesis AMP Stimulates Insulin Activates Protein Kinase Inactivates ACC by phosphorylation Inactivates lipase Activates triacylglycerollipase 35 36 37 Thank you