Lipogenesis Triacylglycerol synthesis Definition Lipogenesis is the synthesis of TAG from fatty acids and glycerol Site Subcellular site cytoplasm Organ tissue site ID: 1032560
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1. Lipogenesis & Lipolysis
2. Lipogenesis Triacylglycerol synthesisDefinition: Lipogenesis is the synthesis of TAG from fatty acids and glycerol.Site:Sub-cellular site: cytoplasmOrgan (tissue) site: liver (primary site), adipose tissue, lactating mammary gland, kidney Esters of glycerol with three fatty acidsFunctions of TriglycerideMain stored from of energy in adipose cells. Energy: 9kcal/gram
3. Synthesis of glycerol phosphate (activation of glycerol): Steps of Lipogenesis
4. Synthesis of acyl-CoA (activation of fatty acids):Fatty acid ------------------------------------------> acyl CoAThiokinaseCoAATP AMP+PiFates of the formed TAGIn liver: TAG VLDL tissues In adipose tissue: TAG stored as depot fat Acyl transferases catalyes the transfer acyl groupsRegulation of lipogenesisInsulin stimulates lipogenesisAdipocytes can take glucose only in the presence of insulinInsulin stimulate glycolysis which supplies glycerol phosphateAnti-insulin hormones inhibit lipogenesis
5. is the hydrolysis or breakdown of triacylglycerol in adipose tissue to glycerol and 3 fatty acidsIt requires enzymes called lipases which are present in the adipose tissue. Site:Sub-cellular site: cytoplasmLipolysisThe hydrolysis of triacylglycerol is initiated by hormone sensitive lipase. HSL is Hormonally regulated
6. Regulation of lipolysisHormone-sensitive lipase (HSL) is activated when phosphorylated by cyclic AMP-dependent protein kinase Epinephrine & other anti-insulin hormones stimulate lipolysis during fasting, stress & hypoglycaemia byactivation of adenylate cyclase forming cAMP Insulin inhibits lipolysis byInhibiting adenylate cyclase enzyme Stimulating phosphodiesteraseStimulating phosphatase enzyme
7. Lipid Metabolism in Fat Cells:Fed State Starved StateInsulinStimulates up-take of glucose by Adipocytes stimulates glycolysisincreased glycerol phosphate synthesisincreases esterificationinactivates HSLnet effect: TG storageGlucagon, epinephrineactivates HSLnet effect: TG mobilization and increased FFAinhibit lipogenesis
8. FATTY ACIDS SYNTHESISDefinition: Synthesis of saturated fatty acidsProduct: palmitate (16 c)Site:Sub-cellular site: cytoplasmOrgan (tissue) site: liver, lactating mammary gland, adipose tissue & kidneyMain requirements:Acetyl CoA (Active Acetate) Acetyl CoA carboxylase enzymeATP for activation & fixation of CO2 in the synthesis of malonyl CoA from acetyl CoANADPHACP Fatty Acid Synthase β-Ketoacyl synthaseβ-Ketoacyl synthase Fatty Acid Synthase ACPSHSHSHSHFatty acid synthase multienzyme complex. It is a dimer. Each unit contains 7 enzymes and a protein (acyl carrier protein)
9. Steps of Fatty acid synthesisTranslocation of acetyl CoA from mitochondria to cytoplasm (Citrate shuttle)B. Cytoplasmic pathway for fatty acid synthesis:Carboxylation of acetyl CoA (2 carbon atoms) to malonyl CoA by acetyl CoA carboxylase (ACC)Formation of palmitate (16 C) by Fatty acid synthase multienzyme complex.
10. Cytoplasmic pathway for fatty acid synthesis:1- Carboxylation of acetyl CoA by Acetyl CoA Carboxylase‘first reaction’ of fatty acid synthesisThis is the irreversible regulatory step in fatty acid synthesismalonyl-CoA serves as activated donor of acetyl groups in FA synthesis
11. 2- Formation of palmitate (16 C):All the next steps are catalyzed by Fatty acid synthasePriming reactions (Transacetylases)(1) Condensation Rxn(2) Reduction Rxn(3) Dehydration Rxn(4) Reduction RxnThioesterase The overall reaction for palmitate synthesis: 1 Acetyl CoA+7 Malonyl CoA+14(NADPH+H†)+7ATP---------Palmitate(16C)+8CoA+14NADP†+7(ADP+Pi)+7H2O
12. REGULATION OF FATTY ACID SYNTHESIS Acetyl CoA---------------------------> Malonyl CoAAllosteric Hormonal Acetyl CoA CarboxylaseCitrate Malonyl CoAPalmitoyl CoAInsuline GlucagonEpinephrine -I- short-term regulation of acetyl CoA carboxylaseHigh-calorie, high- carbohydrate dietsLow-calorie diet or fasting+-II- long-term regulation of acetyl CoA carboxylase-++
13. Catabolic Pathway Of FABeta Oxidation Of Fatty Acids
14. Beta Oxidation of Fatty acids Beta Oxidation is the process where energy is produced by degradation of fatty acids to acetyl-CoA unitsThe process of fatty acid oxidation is termed b oxidation since it occurs through the sequential removal of 2-carbon units (as acetyl-CoA) by oxidation at the b-carbon position of the fatty acyl-CoA molecule. Importance of b-oxidation Energy productionAcetyl-COA production
15. β -oxidation takes place in Mitochondria → Fatty acids which are participating in β-oxidation undergo activation to form Fatty acyl CoA→ Activation of fatty acid takes place in CYTOPLASM, requires 2 high energy bonds and enzyme is Thiokinase or fatty acyl Co A synthetase. 1
16. Transport of acyl CoA into the mitochondria ( rate-limiting step) The activated fatty acids which are present in CYTOPLASM enters into MITOCHONDRIA with the help of CARNITINE CARRIER.FA~CoAFA~CarnitineAcyl transferase IFA~CarnitineCarnitineAcyl transferase IITranslocaseHS-CoAFA~CoAHS-CoACarnitineN(CH3)3CH2H-C-OHCOO-CH2+CarnitineCYTOPLASMTHE MATRIX
17. β – oxidation proper There are 4 steps in β C– oxidation Step I – Oxidation by FAD linked dehydrogenaseStep II – Hydration by HydrataseStep III – Oxidation by NAD linked dehydrogenaseStep IV – Thiolytic clevage Thiolase
18. Beta Oxidation
19. Beta Oxidation
20. Beta OxidationPalmitic (16 c)
21. 21-Oxidation and ATPActivation of a fatty acid requires: 2 ATPOne cycle of oxidation of a fatty acid produces:1 NADH 3 ATP1 FADH2 2 ATPAcetyl CoA entering the citric acid cycle produces:1 Acetyl CoA 12 ATPPalmitic acid (16 C) needs 7 cycles of beta-oxidation, which gives rise to 8 acetyl Co A x 12 = 96 ATP7 FADH2 x 2 = 14 ATP7 NADH x 3 = 21 ATPTotal 131 ATPIn initial activation Palmic acid → Palmitoyl Co A requires 2 high energy phosphates, so net is 131 – 2 = 129 ATP
22. Odd number fatty acids are oxidized by β-oxidation until the final 3 carbons propionyl CoA is produced. So, β- oxidation of odd number fatty acid gives: (n) acetyl CoA + 1 propionyl CoA Propionyl CoA is converted to succinyl CoA which can enter the TCA cycle β- oxidation of odd number fatty acids
23. Ketone BodiesA special source of fuel and energy for certain tissues Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrate These are called "ketone bodies"Source of fuel for brain, heart and muscle Ketogenesis increases in fasting , diabetes and starvation
24. 4/29/11Oxidation of Ketone Bodies for EnergyMost tissues can oxidize ketone bodies-requires mitochondriaConditions that increase KB synthesis and oxidationLength of fasting (> 3 days)Low carb dietsUntreated Type 1 diabetesDiabetic ketoacidosisLiver synthesizes KB but can not oxidize them: liver lacks CoA transferaseENERGY PRODUCTION FROM OXIDATION OF-HYDROXYBUTYRATE
25. Lipid transport
26. Non-covalent assemblies of lipids and proteinsLP coreTriglyceridesCholesterol estersLP surfacePhospholipidsProteinscholesterolPlasma Lipoproteins (Structure)Function as transport vehicles for triacylglycerols and cholesterol in the bloodAll the lipids contained in plasma, including fat, phosphalipids, cholesterol, cholesterol ester and fatty acid, exist and transport in the form of lipoprotein
27. CMVLDLLDLHDLLipoprotein Nomenclature, Composition and seperationMajor apoB 48 apoB 100 apoB 100 apoA-IProteinMajor TG TG CE CELipidElectrophoresis method: - Lipoprotein fast pre -Lipoprotein -Lipoprotein CM (chylomicron) slow2. Ultra centrifugation method：high density lipoprotein (HDL) highlow density lipoprotein ( LDL)very low density lipoprotein ( VLDL) CM (chylomicron ) slow
28. Lipids (Triacylglycerols) are Transported as LipoproteinsIntestinal Mucosa (Exogenous Lipids) ChylomicronsLiver (Endogenous Lipids)VLDL (very low density lipoproteins)
29. Synthesized in small intestineTransport dietary lipids (exogenous TG)98% lipid, large sized, lowest densityApo B-48Receptor bindingApo C-IILipoprotein lipase activatorApo ERemnant receptor bindingChylomicronsNascent chylomicron (B-48)Mature chylomicron (+apo C & apo E)Lipoprotein lipaseChylomicron remnantApo C removedRemoved in liver
30. Synthesized in liverTransport endogenous triglycerides90% lipid, 10% proteinApo B-100Receptor bindingApo C-IILPL activatorApo ERemnant receptor bindingNascent VLDL (B-100) + HDL (apo C & E) = VLDLLPL hydrolyzes TG forming IDL75% of IDL removed by liver25% of IDL converted to LDL by hepatic lipaseVery Low Density Lipoprotein (VLDL)
31. Is both consumed (exogenous) and produced by the liver (endogenous).Endogenous production increases with high ingestion of Saturated fatFound ONLY in animal productsBlood Cholesterol
32. Acetyl CoA is the source of all carbon atoms in cholesterolSqualeneβ -hydroxy- β- methylglutaryl CoA Mevalonate Farmesyl pyrophosphate Acetyl CoA CoAAcetoacetyl CoA CoAAcetyl CoAHMG-CoA reductaseCyclizationInhibition
33. Formation site: from VLDL in blood, but a small part is directly released from liverFunction: transport cholesterol from liver to the peripheral tissues.Carries aprox. 50% of blood cholesterol. containing only apo B-100. LDL concentration in blood has positive correlation with incidence of cardiovascular diseases. Low Density Lipoproteins (LDL - Bad)Fates of cholesterol in the cells1. Incorporated into cell membranes.2. Metabolized to steroid hormones.3. Re-esterified and stored. 4. Expulsion of cholesterol from the cell, and transported by HDL and finally excreted through liver.
34. Formation site: liver and intestineFunction: transport cholesterol from peripheral tissues to liver (reverse cholesterol transport) Reservoir of apoproteins Contain protein, CholesterolProtects against heart diseaseApo AActivates lecithin-cholesterol acyltransferase (LCAT)Apo CActivates LPLApo ERemnant receptor bindingHigh Density Lipoproteins (HDL – Good)Uptake of cholesterol from peripheral tissuesEsterification of HDL-C by LCATTransfer of CE to (IDL and CR) removal of CE-rich remnants by liverconverted to bile acids and excreted
35. a . To combine and transport lipids.b . To regulate lipoprotein metabolism. apo A II activates hepatic lipase（HL） apo A I activates LCAT apo C II activates lipoprotein lipase（LPL）c. To recognize the lipoprotein receptors.Functions of apolipoproteins
36. Apolipoproteins