Lipids and lipoproteins metabolism

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Lipids and lipoproteins metabolism. Outline. 1. Introduction 2. Digestion and absorption in GI 3. Formation and secretion of lipoproteins (chylomicron) by enterocytes 4. Blood circulation and targeting of dietary lipids and lipoproteins 5. Destination of fatty acids in tissues - PowerPoint PPT Presentation

Transcript of Lipids and lipoproteins metabolism

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  • Lipids and lipoproteins metabolism*

  • Outline1. Introduction2. Digestion and absorption in GI3. Formation and secretion of lipoproteins (chylomicron) by enterocytes4. Blood circulation and targeting of dietary lipids and lipoproteins5. Destination of fatty acids in tissues6. Lipid transport in fed state7. Lipid transport in fasted state8. Oxidation of fatty acids

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  • 1. Importance of lipids and lipoproteinsHeterogeneous group of water insoluble organic moleculesMajor source of energy (9Kc/1gr)Storage of energy (TAG in adipose tissue)Amphipatic barriers (PL, FC)Regulatory or coenzyme role (vitamins)Control of bodys homeostasis (steroid hormones, PG)Consequences of imbalance in lipids and lipoproteins metabolism:AtherosclerosisObesityDiabetes

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  • 1. Importance of lipids and lipoproteins*AtherosclerosisObesity

  • Lipid metabolism2. Digestion and absorption of Dietary fatsinGI*

  • 2.1. Dietary fats contentsTriacylglycerol (TAG)Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG) or TAGCholesterol (FC, CE)Phospholipids (PL)Free fatty acids (FFA)*

  • 2.2. Dietary sources of LipidsAnimal Sources

    Vegetable Sources

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  • *General schematic

  • 2.3. Digestion of dietary fatsDigestion in stomachLingual lipase -----acid stableGastric lipase -----acid stableThese enzymes are most effective for short and medium chain fatty acidsMilk, egg yolk and fats containing short chain fatty acids are suitable substrates for its actionPlay important role in lipid digestion in neonates*

  • 2.4.Digestion in small intestine*

  • 2.5. Bile SaltsBile salts are synthesized in the liver and stored in the gallbladder They are derivatives of cholesterolBile salts help in the emulsification of fatsBile salts help in combination of lipase with two molecules of a small protein called as Colipase. This combination enhances the lipase activity*

  • 2.6. Pancreatic enzymes in degradation of dietary lipidsPancreatic Lipase (along with colipase)Degradation of TAGCholesteryl estraseDegradation of cholesteryl estersPhospholipase A2 and lysophospholipase- Degradation of Phospholipids*

  • 2.6. Pancreatic enzyme*PLase A2

  • 2.7. Controlof lipid digestionCholecystokininSecretinBicarbonate

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  • 2.8. Disorders1. Lithiasis 2. Cystic fibrosis

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  • 2.8. Disorders: Lipid MalabsorptionSteatorrhea: increased lipid and fat soluble vitamin excretion in feces.Possible causes of steatorrehea

    * Colipase deficiency

  • 3. Absorption and secretion of lipids by enterocytes*TAG: triacylglycerolDAG: diacylglycerolMAG: monoacylglycerolFA: fatty acidCL: cholesterolBS: bile saltLPA: lysophosphatidateCE: cholestryl esterACAT: acyl-CoA cholesterol acyl transferaseCM: chylomicronMTP: microsomal TAG transfer proteinAGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase

  • 3. Secretion of lipids from enterocytesAfter a lipid rich meal, lymph is called chyle

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  • 4. Blood circulation and targeting of dietary lipids and lipoproteins*

  • 4. Blood circulation and targeting of lipids and lipoproteins*

  • 4.1. ApoC-II, lipoprotein lipase (LPL) , deficiency and heparan sulfate*GlycerolChylomicron remnantLPLHDLLiver(exogenous)Clearing factor

  • 6. Destination of fatty acids in tissuesMuscle tissue and liver: Catabolism (oxidation)The end product of FAs catabolism (acetyl-CoA):as fuels for energy production (TCA)as substrates for cholesterol and ketone body synthesisAdipose tissue: Storage (TAG)*

  • 7. Lipids and lipopoteins transport in fed state*FAs

    TAGsFAs energy Chylomicron (TAGendo) and VLDL (TAGexo) Acetyl-CoA FAs TAGBlood streamMuscle Adipose tissueliverSmall intestineChylomicronVLDL

  • * 8. Lipids and lipopoteins transport in long fasted stateFAs+Glycerol

    TAGsFAs(+ketone bodies) energy FAs-albumin glycerol FAs

    Acetyl-CoA

    Ketone bodiesBlood streamMuscle Adipose tissueliverGlucose GlycerolKetone bodies

    Acetyl-CoA

    energy

    ketone bodies Brain

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  • Pathway for catabolism of saturated fatty acids at the carbon atom with successive removal of two carbon atoms as acetyl CoASite: Cytosol (activation)MitochondriaMembrane transportMatrix ( oxidation)

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  • 9.1.1. Activation and transport of fatty acids into mitochondria*Acyl CoA synthase

  • 9.1.1. Entry of short and medium chain FA into mitochondriaCarnitine and CAT system not required for fatty acids shorter than 12 carbon length.

    They are activated to their CoA form inside mitochondrial matrix.

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  • 9.1.1.1. Carnitine deficienciesPrimary causes:Carnitine acyl transferase-I (CAT-I) deficiency: mainly affects liverCarnitine acyl transferase-II (CAT-II) deficiency: mainly affects skeletal and cardiac muscles.Secondary causes :liver diseases: decreased endogenous synthesis

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  • 9.1.1.1. Consequence of carnitine deficienciesExcessive lipid accumulation occurs in muscle, heart, and liverCardiac and skeletal myopathyHepatomegalyLow blood glucose in fasted state hypoglycemia coma*

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  • Provision of energyMajor pathway of acetyl-CoACholesterol productionKetone bodies productionDiabetesStarvation

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  • Types of fatty acyl CoA dehydrogenasesLong chain fatty acyl CoA dehydrogenase (LCAD)Medium chain fatty acyl CoA dehydrogenase (MCAD)Short chain fatty acyl CoA dehydrogenase (SCAD) MCAD deficiency is thought to be one of the most common inborn errors of metabolism.

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    TAG FFAGlucagon Epinephrine+The first levelThe second levelFFAAcetyl-CoATCANADHThe third levelCAT1FFAMalonyl-CoA-Acetyl-CoA and NADH inhibition of oxidation enzymes Adipose tissueMuscle tissue and liver -Insulin

  • Peroxisomal FA oxidationActs on very long chain fatty acids (VLCFAs)Zellweger syndromeAbsence of peroxisomesRare inherited disorderVLCFA cannot be oxidized Accumulation of VLCFA in brain, blood and other tissues like liver and kidney*

  • Omega oxidationIt is a minor pathwayTakes place in microsomesInvolves oxidation of last carbon atom ( carbon)More common with medium chain fatty acids

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  • Alpha oxidationSeen in branched chain fatty acid, phytanic acidOccurs in endoplasmic reticulumRefsum diseaseGenetic disorder Caused by a deficiency of alpha hydroxylaseThere is accumulation of phytanic acid in the plasma and tissues.The symptoms are mainly neurological.

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  • Acetyl CoA and lipid metabolism*TCAPentose phosphate pathwayMitochondriaCytosol

  • De Novo synthesis of fatty acidsSaturated fatty acids are synthesized from acetyl CoA Occurs in cytoplasmOccurs mainly in liver, adipose tissue and lactating mammary glandNeed toacetyl CoANADPH

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  • De Novo synthesis of fatty acidsPhase ITransport of substrates into cytosolCarboxylation of acetyl-CoA to malonyl-CoAPhase IIUtilization of substrate to form palmitate by fatty acid synthase complexPhase IIIElongation and desaturation of palmitate to generate different fatty acids

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  • Acetyl CoA activation and regulation of it*Glucagon and epinephrine+

  • Synthesis of palmitate by fatty acid synthase(FAS) *

  • Modification of dietary and endogenous fatty acidsChain elongation to give longer fatty acids

    Desaturation, giving unsaturated fatty acids*

  • Modification of dietary and endogenous fatty acids*Essential fatty acids

  • *Acyl-CoACoAAcyl-CoACoAPiAcyl-CoACoAAcyl-CoACoAAcyl-CoACoAATPADPNADH, H+NAD+NADH, H+NAD+

  • Fates of TAG in liver and adipose tissueAdipose tissue: TAG stored in cytosolLiver: very little stored. Exported out of liver in VLDL , which exports endogenous lipids to peripheral tissues

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  • *FFA LipogenesisLipolysisLipolysis

  • Mobilization of stored fats and release of FAs*HSLPPPPPPGlucagon & epinephrine

  • Metabolism of cholesterol*

  • Cholesterol*

  • Cholesterol importanceMembrane componentSteroid synthesisBile acid/salt precursorVitamin D precursorIt is synthesized in many tissues from acetyl-CoA and is eliminated from the body in the bile salts

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  • Liver cholesterol poolDietDe novo synthesisCholesterol synthesized in extrahepatic tissuesLiver cholesterol poolFree cholesterolIn bileConversion to bile salts/acidsSecretion of HDLand VLDL*

  • Cholesterol SynthesisOccurs in cytosolRequires NADPH and ATP All carbons from acetyl-CoAHighly regulatedSite : Liver, adrenal cortex, testis, ovaries And intestine.All nucleated cells can synthesize cholesterol.Area :The enzymes of synthesis are located partly in endoplasmic reticulum and partly in cytoplasm. *

  • Cholesterol Synthesis*

  • Regulation of Cholesterol synthesisCovalent modification*

  • Regulation of Cholesterol synthesisRegulation at transcription

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  • Lipoprotein metabolism*

  • CORECHOLESTEROLESTERSTRIGLYCERIDESMONOLAYER OF PHOSPHOLIPID AND CHOLESTEROLINTEGRAL APOPROTEINSPERIPHERAL APOPROTEINSStructure of lipoprotein*

  • Apoproteins*

    A BCEA-I Liver& intestineA-II LiverB-48 IntestineB-100 LiverC-lC-llC-lllAll LiverLiver

  • ClassificationBased on density by ultracentrifugationChylomicronsVery Low Density LipoproteinIntermediate Density LipoproteinLow Density LipoproteinHigh Density Lipoprotein*

  • Composition and size of lipoprotein*

  • Lipoprotein function *

  • Exogenous cycle(Metabolism of CM)*

  • Endogenous cycle(VLDL)*

  • HDL- cholestrol metabolismreverse cholesterol transport andLDL metabolism*

  • Regulated: by LDL receptor

    Unregulated : by scavenger receptor(SR)*

  • Regulated: by LDL receptor*

  • regulatedLDL uptake byLDL receptor

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  • Antioxidants Free radicalsScavenger receptorUnregulated LDL uptake by scavenger receptor *

  • Atherosclerosis is a form of arteriosclerosis in which thickening and hardening of the vessel are caused by the accumulation of lipid-laden macrophages or foam cell within the arterial wall, which leads to the formation of a lesion called a plaqueAtherosclerosis is not a single disease

    It is the leading contributor to coronary artery and cerebrovascular diseaseAtherosclerosis*

  • Atherosclerosis*

  • HypercholesterolemiaNormal serum cholesterol level 150-200mg/dlIncreased cholesterol level is seen in following conditions diabets mellitus, lipid nephrosis, hypothyroidism AtherosclerosisXanthomas (deposition of cholesterol in subcutaneous tissue)Corneal arcus (deposits of lipid in cornea)*

  • Fredrickson classification of the hyperlipidemias*

  • Degradation of Cholesterol Synthesis of bile acids Excretion in the feces*

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  • Cholesterol-lowering drugsStatinsFibric acid derivativesNiacinBile-acid resinsCholesterol absorption inhibitors

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  • Ketone bodies*

  • Ketone bodiesKetone bodies are metabolic products that are produced in excess during excessive breakdown of fatty acids

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  • Ketone bodies importanceAlternate sources to glucose for energyProduction of ketone bodies under conditions of cellular energy deprivationUtilization of ketone bodies by the brain

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  • ketone bodies production and utilization*HMG-CoA synthase

  • By availability of acetyl CoALevel 1Lipolysis Level 2Entry of fatty acid to mitochondriaLevel 3Oxidation of acetyl CoA

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  • Diabetic Ketoacidosis*With each ketone body, one hydrogen atom is released in bloodlowering of pH Acidosis.

  • Metabolism of complex lipidsPhospholipidsPolar, ionic compoundsalcoholPhosphodiester bridgeDiacylglycerol or SphingosineTypes:GlycerophospholipidsSphingophospholipids (sphingosine)

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  • Synthesis of phospholipidsSynthesized in smooth endoplasmic reticulum.Transferred to Golgi apparatusMove to membranes of organelles or to the plasma membrane or released out via exocytosisAll cells except mature erythrocytes can synthesize phospholipids*

  • Synthesis of GlycerophospholipidsBiosynthesis of anionic GlycerophospholipidsPhosphatidylglycerol(PG)Phosphatidylinositol(PI)CardiolipinBiosynthesis of neutral glycerophospholipidsPhosphatidylcholine(PC)Phosphatidylethanolamine(PE)

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  • Synthesis of GlycerophospholipidsFirst strategy: biosynthesis of anionic GlycerophospholipidsCTP:phosphatidate citidyl transferase:

    *Alcohol CMP R1R2OPR1R2CDPR1R2phosphoalcoholCTP PPi

  • Synthesis of GlycerophospholipidsSecond strategy:Biosynthesis of neutral glycerophospholipidsCTP:phospho alcohol citidyl transferase:

    *R1R2OHR1R2phosphoalcohol

  • Sphingophospholipids*

  • Sphingomyelin synthesisCeramide is required for sphingomyelin synthesis*PCDAG

  • Degradation of glycerophospholipidsPhospholipases remove one fatty acid from C1 or C2 and form lysophosphoglyceride.Lysophospholipases act upon lysophosphoglycerides.Phospholipase A1Phospholipase A2Phospholipase CPhospholipase D*

  • Phospholipases*

    Phospholipse ProductSignificantA1FA--- 1-lysophospholipidPhospholipid transformationA2FA--- 2-lysophospholipidPhospholipid transformation, Eicosanoid synthesisBFA---- Glycerol 3-phosphoalcoholLysophospholipid degradationCPhosphoalcohol---1,2DAGSecondary messenger productionDAlcohol---- phosphatidic acidSecondary messenger production

  • Degradation of SphingomyelinSphingomyelinaseCeramidaseSphingosine and ceramide act as intracellular messengers.

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  • GlycolipidsCarbohydrate and lipid componentsDerivatives of ceramideEssential components of all membranes, greatest amount in nerve tissueInteract with the extracellular environmentNo phospholipid but oligo or mono-saccharide attached to ceramide by O-glycosidic bond.*

  • Classes of GlycosphingolipidsNeutral glycosphingolipids :CerebrosidesGlobosidesAcidic glycosphingolipids:GangliosideSulfatides *

  • Synthesis of Neutral GlycosphingolipidsSite:Golgi apparatusSubtratesCeramide, sugar activated by UDPGalactocerobrosides Ceramide + UDP- galactoseGlucocerebrosides Ceramide + UDP glucoseEnzymes Glycosyl transferases*

  • Synthesis of Acidic Glycosphingolipids Gangliosides ceramide + two or more UDP- sugars react together to form Globoside.NANA combines with globoside to form Ganglioside.*

  • Synthesis of Acidic Glycosphingolipids Sulfatidesgalactocerebroside gets a sulphate group from a sulphate carrier with the help of sulfotransferase and forms a sulfatide.

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  • Degradation of glycosphingolipidsDone by lysosomal enzymes

    Different enzymes act on specific bonds hydrolytically ---- the groups added last are acted first.

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  • SphingolipidosesLipid storage diseasesAccumulation of sphingolipids in lysosomesPartial or total absence of a specific hydrolaseAutosomal recessive disorders

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  • *Degradation of glycosphingolipids

  • Eicosanoids are classified in to two main groups- 1) Prostanoids 2) Leukotrienes and Lipoxins Prostanoids are further sub classified in to three groups- a) Prostaglandins(PGs) b) Prostacyclins(PGIs) c) Thromboxanes (TXs) Eicosanoids- Classification

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  • Characteristic features of prostaglandinsAct as local hormonesShow the autocrine and Paracrine effectsAre not stored in the bodyHave a very short life span and are destroyed within seconds or few minutesProduction increases or decreases in response to diverse stimuli or drugsAre very potent in action. Even in minute (ng concentration), biological effects are observed. *

  • Synthesis of eicosanoidsLinoleic acid is the dietary precursor of PGs.Arachidonic acid is formed by elongation and desaturation of linoleic acid.Membrane bound phospholipids contain arachidonic acid.Phospholipase A2 causes the release of arachidonic acid from membrane phospholipids. *

  • Synthesis of eicosanoids *Steroidic anti- inflammation drugs NSAIDs

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