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Lipid Chemistry

Lipid Chemistry . Dr. S.Chakravarty MD . Specific Learning objectives:. At the end of this session the student should be able to :- List the various lipases acting on triglycerides in different parts of the body List the components of Phospholipids and Glycolipids

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Lipid Chemistry

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  1. Lipid Chemistry Dr. S.Chakravarty MD

  2. Specific Learning objectives: • At the end of this session the student should be able to :- • List the various lipases acting on triglycerides in different parts of the body • List the components of Phospholipids and Glycolipids • Describe the properties of Omega 3 and omega 6 fatty acids • Describe the Functions of phospholipase A2 and C • Classify the types of Phospholipids and Glycolipids • Analyse the Composition of surfactant and its importance • Describe the Sphingolipid metabolism and the enzyme deficient in various sphingolipidoses

  3. Functions of lipids: • Important form of energy storage (9.1 kcal/g) • 30% daily energy requirements of the body • Phospholipids are components of Biomembrane • Major regulatory hormones – Steroids • Storage and absorption of FAT soluble vitamins – A,D,E,K. • Act as second messengers – Diacyl glycerol.

  4. Cont.. • Non polar lipids – myelin sheath – electrical insulator • Inflammatory mediators – Eicosanoids • Thermal insulators • Lipoproteins – transport proteins • Pathogenesis of DM, obesity, atherosclerosis • TASTE – palatability of food

  5. Source of energy Protection Lipoproteins Lipids Bile salts Thermal & Electrical insulator Hormones Prostaglandins Vitamins

  6. OBESITY metabolic syndrome diabetes mellitus atherosclerosis

  7. Classification of Lipids LIPIDS COMPLEX (COMPOUND) LIPIDS Derived Lipids SIMPLELIPIDS

  8. Classification :modified from Bloor 1.Simple lipids : Esters of fatty acids with various alcohols. a. Neutral Fats: Esters of fatty acids with glycerol. uncharged. Eg.- triolein, tripalmitin. Diet - triglycerides. Oils - Fats in the liquid state. Eg.- corn, groundnut oil. b. Waxes: Esters of fatty acids(c14 – 36) with higher M.wt monohydric long chain alcohols.( c16 - 30) . Eg. Bees wax, lanolin, spermaceti oil. Used for lotions, ointments

  9. CH3(CH2)14 C =OO CH2 (CH2)28 CH3 Palmitic acid 1-Triacontanol Triacontanoylpalmitate, the major component of beeswax.

  10. II)Complex Lipids : Esters of fatty acids with alcohol + containing additional groups (prosthetic group). a. Phospholipids : Fatty acids ,alcohol and a phosphate group , nitrogen containing bases and other substituents.eg, Glycerophospholipids the alcohol is glycerol Sphingophospholipids the alcohol is sphingosine. b. Glycolipids(glycosphingolipids) : fatty acid, sphingosine and carbohydrate with nitrogen base. c. Other complex lipids: Lipoproteins , sulfolipids and aminolipids.

  11. III) Precursor and Derived lipids : Derived from simple lipids or complex lipids on hydrolysis. A)fatty acids, glycerol,Monoacyl and Diacylglycerol. B) Steroids- lipids with cyclo pentano perhydrophenanthrene (steroid) ring. Eg. – cholesterol and its derivatives- bile acids, hormones, Ergosterol. C)Eicosanoids – Arachidonic acid derivatives- PG,TXA2, LTB. D)Terpenes – Isoprene units – 5 Carbon compoundEg.- Carotenes, vitamins A,E,K and Dolichol , CO-Q, Squalene .

  12. IV) Others : Fatty aldehydes, ketone bodies, hydrocarbons and other alcohols.

  13. Triglycerides : • Storage form of fat in the adipose tissue. • Synthesized mainly in liver, adipose tissue and lactating mammary. • Acted upon by lipases: • Pancreatic • Lipoprotein – endothelium close to organs • Hormone sensitive – Adipose tissue • Hepatic - liver Neutral lipids - uncharged . Eg. acylglycerols , cholesterol, and cholesteryl esters .

  14. Structure of fatty acid : Methyl end or omega carbon Carboxylic acid end • Aliphatic unbranchedMonocarboxylic acids:

  15. Nomenclature of fatty acids: • Nomenclature: • Delta (∆) naming: carbon ∆1 is carboxyl, ∆ 2 is called α carbon, ∆ 3 is b carbon, etc. • w carbon numbering - terminal methyl group is always the omega carbon one. Number in the bracket is first double bond from omega i.e. w(3).

  16. Fatty acids: • Bound with albumin in blood circulation – FFA (NEVER FREE!!) • Saturated – no double bonds – mostly solids Unsaturated – double bonds – mostly liquids PUFA – Essential fatty acids. • Orientation around double bonds – cis and trans

  17. Classification of fatty acids based on chain length: • Short-chain fatty acids - Fewer than six carbons • Medium-chain fatty acids (MCFA) - 6–12 c • Long-chain fatty acids (LCFA) longer than 12 c • Very-Long-chain fatty acids (VLCFA) longer than 20 c • Eicosanoids –Derived and modified from 20 c Arachidonic acid.

  18. ClASSIFICATIONOn the basis of no. of `C` atoms – even, odd • Even number- e.g.-Palmitic acid / hexadecanoic acid , stearic acid. • Odd number –e.g.-Propionic acid, Valeric acid • e.g.- Acetic acid - CH3COOH Propionic acid – C2H5COOH

  19. Trans fat- HARMFUL • Theory :-Trans fat not broken by LIPASE- Body can’t metabolize it . • Deposition in the blood vessels. • Partial hydrogenation of unsaturated oils – leads to trans fats. • Free radical generation.

  20. Essential fatty acids: • ω-3 fatty acids: α-Linolenic acid  (18:3) 9, 12, 15 • ω-6 fatty acids: Linoleic acid  (18:2)9,12 Why essential? • Lack the ability to introduce double bonds in fatty acids beyond carbon ∆ 9 and 10. • Δ9desaturase, Δ6desaturase, Δ5desaturase, and Δ4desaturase are present in the body.

  21. Saturated fatty acid 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Omega 9 fatty acid 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Omega 6 fatty acid 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Omega 3 fatty acid

  22. These EFA can be synthesized by chain elongation of linoleic and linolenic acid. • ω-3 fatty acids: α-Linolenic acid • Eicosapentaenoic acid or EPA (20:5) • Docosahexaenoic acid or DHA (22:6) • ω-6 fatty acids:Linoleic acid • Gamma-linolenic acid or GLA (18:3) • Arachidonic acid or AA (20:4) ω-9 fatty acidsare not essential in humans, because humans generally possess all the enzymes required for their synthesis

  23. Phospholipids: • Derivative of phosphatidic acid. • Types – glycerol / sphingol as alcohol. • Chief component of plasma membrane. • Forms micelles- polarity. Phosphate (hydrophilic) Glycerol Fatty acid (hydrophobic)

  24. Phospholipases: on Membrane phospholipids CH2 A1 Saturated fatty acid (Palmitic acid) F1 1 B A2 Unsaturated fatty acid (Arachidonic acid) CH F2 2 PO4 Inositol C D PO4 CH2 PO4 3 PhosphatidylInositol 4,5 Bisphosphate

  25. Phospholipases: • Phospholipase A: • Phospholipase A1 - cleaves the SN-1 acyl chain • Phospholipase A2 - cleaves the SN-2 acyl chain releasing Arachidonic acid • Phospholipase B - cleaves both SN-1 and SN-2 acyl chains, also known as a lysophospholipase • Phospholipase C - cleaves before the phosphate, releasing Diacyl glycerol and Inositol triphosphate • Phospholipase D - cleaves after phosphate, releasing phosphatidic acid.

  26. Dipalmitoyl lecithin : • Dipalmitoylphosphatidylcholine– acts as a surfactant in lungs • Reduces surface tension of alveoli • Absence – respiratory distress syndrome. • Mainly seen with preterm infants born before 32 wks gestation.

  27. Sphingomyelin: • Ceramide = Fatty acid + Sphingosine (alcohol) • Present in brain and nervous tissues.

  28. Liposomes : • Principle of lipoproteins as carriers • Bile salts – emulsification of fat • Drug targeting- specified organs – treatment of Cancer • Gene therapy

  29. Cholesterol :Very Important for Body • Cell membrane • Synthesis of steroid hormones • Synthesis of vitamin D • Synthesis of bile salts Cyclopentanoperhydrophenanthrene ring

  30. Glycolipids • Ceramide + carbohydrate moiety • Ceramide = Fatty acid + Sphingosine (alcohol) • Present in central and peripheral nervous system and as cell surface antigens on plasma membrane. • Cerebrosides – Ceramide +Galactose/Glucose • Gangliosides – Cerebrosides + Sialic acid (9 carbon sugar – NANA). • Fatty acid is usually Cerebronic acid.

  31. Gangliosides – clinical importance • Haemagglutinin of Influenza virus exploits certain gangliosides to enter and infect the cells expressing them. • Tay-Sachs Disease involves accumulation of GM 2 gangliosides due to def of hexosaminidase. • Guillain-Barré syndrome- anti ganglioside antibody. • Cholera toxin – acts through GM1 ganglioside.

  32. Ceramide Synthesis of Sphinolipids Glycolipid synthesis Phospholipid synthesis Phosphatidyl -Choline UDP-Glucose UDP- Galactose Diacylglyverol Sphingomyelin Cerebrosides Sialic acid (NANA) Gangliosides GM2 Gangliosides N-acetyl Galactosamine-NANA-glu-gal-ceramide

  33. Sphingolipidosis : No hepatomegaly (X LINKED RECESSIVE ) USMLE!! • Enzyme deficiencies usually cause death within the first few months of life except adult form of Gaucher and Fabry. Harper

  34. Tay –sachs disease: • Accumulation of GM2 gangliosides • Def of enzyme – Hexosaminidase • Absence of hepatospleenomegaly. • Characteristic cherry red spot on ophthalmoscopy. • Swelling of nerves – due to accumulation. • (dysarthria), (dysphagia), (ataxia), and spasticity – muscle degenration.

  35. Gaucher disease: • Deficiency of enzyme B-glucosidase or Glucocerebrosidase. • Accumulation of Glucocerebrosides in lysosomes of spleen, liver, kidneys, lungs, brain and bone marrow. • Hepatomegaly and Splenomegaly. • Mental Retardation • Hypersplenism – rapid destruction of RBCs, WBCs and platelets. • Osteoporosis – erosion of long bones in 75 % cases.

  36. Niemann–Pick disease • Def of enzyme sphingomyelinase. • Accumulation of sphingomyelin in the liver, spleen, - hepatospleenomegaly, thrombocytopenia. • Cherry red spot and zebra bodies/foamy macrophages. • Accumulation in CNS – ataxia, dysarthria, dysphagia  mental retardation. • FATAL in EARLY LIFE

  37. Krabbe’s disease • Deficiency of enzyme B- Galactosidase or Galctosylcerebrosidase • Accumulation of Galactocerebrosides. • Grouping of Multinucleate globoid cells • Total absense of myelin in schwann and oligodendroglia. • Severe damage to nervous system – appears like cerebral palsies

  38. Fabry disease : • Only X-linked recessive sphingolipidosis • Def of enzyme – αgalactosidase • Accumulation of Globotriaosylceramide in blood vessels and tissues • Classical features: • Burning extremity pain- blood supply to nerves affected • Renal failure • Cardiac failure – hypertrophy of septum • Angiokeratomas – papules on the skin • Reddish purple skin rash.

  39. MCQ1 • A one-year-old baby presents with increasing flaccid paralysis, lack of coordination, and hyporeflexia. Over the next several years, the child's condition deteriorates to a bedridden vegetative state. Funduscopic examination reveals optic atrophy. Extensive enzymologicalstudies document a deficiency of arylsulfatase A (cerebrosidesulfatase) in leukocytes. Which of the following is the most likely diagnosis? A. Gaucher's disease B. Krabbe's disease C. Metachromatic leukodystrophyD. Niemann-Pick disease E. Tay-Sachs disease

  40. MCQ2 • A two year old boy is brought to the OPD with hepatosplenomegaly and mental retardation.He is also having erosion of long bones. A liver biopsy showed accumulation of glucosylseramide in liver cells. The abnormality lies in which of the following enzymes ? • Hexosaminidase A • Arylsulfatase A • Sphingomyelinase • Beta-glucosidase • Alpha –galactosidase

  41. Thank you

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