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Lipids and

lipoproteins metabolism

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Outline

1. 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 lipoproteins• Heterogeneous group of water insoluble organic molecules• Major source of energy (9Kc/1gr)• Storage of energy (TAG in adipose tissue)• Amphipatic barriers (PL, FC)• Regulatory or coenzyme role (vitamins)• Control of body’s homeostasis (steroid hormones, PG)• Consequences of imbalance in lipids and lipoproteins

metabolism:– Atherosclerosis– Obesity– Diabetes

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1. Importance of lipids and lipoproteins

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AtherosclerosisObesity

Lipid metabolism

2. Digestion and absorption of

Dietary fatsinGI

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2.1. Dietary fats contents

• Triacylglycerol (TAG)– Over 93% of the fat that is consumed in the diet is

in the form of triglycerides (TG) or TAG

• Cholesterol (FC, CE)• Phospholipids (PL)• Free fatty acids (FFA)

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2.2. Dietary sources of Lipids

• Animal Sources

• Vegetable Sources

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General schematic

2.3. Digestion of dietary fats

Digestion in stomachLingual lipase -----acid stableGastric lipase -----acid stable

• These enzymes are most effective for short and medium chain fatty acids

• Milk, egg yolk and fats containing short chain fatty acids are suitable substrates for its action

• Play important role in lipid digestion in neonates

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2.4.Digestion in small intestine

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2.5. Bile Salts

Bile salts are synthesized in the liver and stored in the gallbladder

They are derivatives of cholesterol Bile salts help in the emulsification of fats Bile salts help in combination of lipase with two

molecules of a small protein called as Colipase. This combination enhances the lipase activity

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2.6. Pancreatic enzymes in degradation of dietary lipids

• Pancreatic Lipase (along with colipase)

– Degradation of TAG• Cholesteryl estrase– Degradation of cholesteryl esters• Phospholipase A2 and

lysophospholipase- Degradation of Phospholipids

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2.6. Pancreatic enzyme

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PLase A2

2.7. Controlof lipid digestion

CholecystokininSecretinBicarbonate

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2.8. Disorders

1. Lithiasis 2. Cystic fibrosis

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2.8. Disorders: Lipid Malabsorption• Steatorrhea: increased lipid and fat soluble

vitamin excretion in feces.– Possible causes of steatorrehea

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• Colipase deficiency

3. Absorption and secretion of lipids by enterocytes

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TAG: triacylglycerolDAG: diacylglycerolMAG: monoacylglycerolFA: fatty acidCL: cholesterolBS: bile saltLPA: lysophosphatidateCE: cholestryl ester

TAG: triacylglycerolDAG: diacylglycerolMAG: monoacylglycerolFA: fatty acidCL: cholesterolBS: bile saltLPA: lysophosphatidateCE: cholestryl ester

ACAT: acyl-CoA cholesterol acyl transferaseCM: chylomicronMTP: microsomal TAG transfer proteinAGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase

ACAT: acyl-CoA cholesterol acyl transferaseCM: chylomicronMTP: microsomal TAG transfer proteinAGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase

3. Secretion of lipids from enterocytes

After a lipid rich meal, lymph is called chyle

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4. Blood circulation and targeting of dietary lipids and lipoproteins

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4. Blood circulation and targeting of lipids and lipoproteins

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4.1. ApoC-II, lipoprotein lipase (LPL) , deficiency and heparan sulfate

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Glycerol

Chylomicron remnant

LPL

HDL

Liver(exogenous)

Clearing factor

6. Destination of fatty acids in tissues

• Muscle 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 synthesis

• Adipose tissue: Storage (TAG)

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7. Lipids and lipopoteins transport in fed state

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FAs

TAGs

Dietary TAG

FAs energy

Chylomicron (TAGendo) and VLDL (TAGexo)

Acetyl-CoA FAs TAG

Glucose & other fuels

Blood stream

Muscle

Adipose tissue

liverSmall intestine

Chylomicron

VLDL

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8. Lipids and lipopoteins transport in long fasted state

FAs+Glycerol

TAGsFAs(+ketone bodies) energy

FAs-albumin glycerol

FAs

Acetyl-CoA

Ketone bodies

Blood stream

Muscle

Adipose tissue

liver

Glucose

Glycerol

Ketone bodies

Acetyl-CoA

energy

ketone bodies

Brain

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• Pathway for catabolism of saturated fatty acids at the β carbon atom with successive removal of two carbon atoms as acetyl CoA

• Site: – Cytosol (activation)– Mitochondria

• Membrane transport• Matrix ( β oxidation)

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9.1.1. Activation and transport of fatty acids into mitochondria

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Acyl CoA synthase

9.1.1. Entry of short and medium chain FA into mitochondria

• Carnitine 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 deficiencies

• Primary causes:– Carnitine acyl transferase-I (CAT-I) deficiency: mainly

affects liver– Carnitine 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 deficiencies

• Excessive lipid accumulation occurs in muscle, heart, and liver

• Cardiac and skeletal myopathy• Hepatomegaly• Low blood glucose in fasted state hypoglycemia

coma

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• Provision of energy– Major pathway of acetyl-CoA

• Cholesterol production• Ketone bodies production

– Diabetes– Starvation

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Types of fatty acyl CoA dehydrogenases

• Long 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 FFA

Glucagon Epinephrine

+

The first level

The second level

FFAAcetyl-CoA

TCANADH

The third level

CAT1

CAT1

FFA

Malonyl-CoA

-

Acetyl-CoA and NADH inhibition of ᵦ oxidation enzymes

Adipose tissue

Muscle tissue and liver

-

Insulin

Peroxisomal FA oxidation

• Acts on very long chain fatty acids (VLCFAs)• Zellweger syndrome

– Absence of peroxisomes– Rare inherited disorder– VLCFA cannot be oxidized – Accumulation of VLCFA in brain, blood and other

tissues like liver and kidney

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Omega oxidation

• It is a minor pathway• Takes place in microsomes• Involves oxidation of last carbon atom ( ω

carbon)• More common with medium chain fatty acids

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Alpha oxidation• Seen in branched chain fatty acid, phytanic acid• Occurs in endoplasmic reticulum• Refsum disease

– Genetic disorder – Caused by a deficiency of alpha hydroxylase

– There is accumulation of phytanic acid in the plasma and tissues.

– The symptoms are mainly neurological.

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Acetyl CoA and lipid metabolism

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TAG- Protein -Glucose

Acetyl-CoA

TCA

Ketone bodies

HMG-CoA

GLCProtein

TAG & PL

HMG-CoA

Cholesterol

Pentose phosphate pathway

FA

Mitochondria Cytosol

De Novo synthesis of fatty acids

• Saturated fatty acids are synthesized from acetyl CoA

• Occurs in cytoplasm• Occurs mainly in liver, adipose tissue and

lactating mammary gland• Need to

– acetyl CoA– NADPH

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De Novo synthesis of fatty acids

• Phase I– Transport of substrates into cytosol– Carboxylation of acetyl-CoA to malonyl-CoA

• Phase II– Utilization of substrate to form palmitate by fatty

acid synthase complex• Phase III

– Elongation and desaturation of palmitate to generate different fatty acids

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Acetyl CoA activation and regulation of it

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Glucagon and epinephrine

+

Synthesis of palmitate by fatty acid synthase(FAS)

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Modification of dietary and endogenous fatty acids

• Chain elongation to give longer fatty acids

• Desaturation, giving unsaturated fatty acids

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Modification of dietary and endogenous fatty acids

45ω-7 ω-9

ω-6 ω-3Essential fatty acids

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GlycerolGlucose

Dihydroxy acetone phosphate

1acyl-dihydroxy acetone phosphate

Pyruvate Glycerol 3-P

1acyl- glycerol 3-P

1,2Diacyl- glycerol 3-P (phosphatidate)

Diacylglycerol

TAG

Monoacylglycerol

Acyl-CoA

CoA

Acyl-CoACoA

Pi

Acyl-CoACoA

Acyl-CoA

CoA

Acyl-CoACoA

ATPADPNADH, H+ NAD+

NADH, H+ NAD+

TAG formation

Fates of TAG in liver and adipose tissue

• Adipose tissue: TAG stored in cytosol• Liver: very little stored. Exported out of liver in VLDL ,

which exports endogenous lipids to peripheral tissues

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FFA Lipogenesis

Lipolysis

Lipolysis

Mobilization of stored fats and release of FAs

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HSLHSL-P

P

P P

P

P

P

Glucagon & epinephrine

+

Metabolism of

cholesterol50

Cholesterol

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Cholesterol importance

• Membrane component• Steroid synthesis• Bile acid/salt precursor• Vitamin D precursor• It is synthesized in many tissues from acetyl-CoA and

is eliminated from the body in the bile salts

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Liver cholesterol pool

Diet De novo synthesisCholesterol synthesized in extrahepatic tissues

Liver cholesterol pool

Free cholesterolIn bile

Conversion to bile salts/acidsSecretion of HDLand VLDL

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Cholesterol Synthesis

• Occurs in cytosol

• Requires NADPH and ATP

• All carbons from acetyl-CoA

• Highly regulated• Site : 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.

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Cholesterol Synthesis

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Regulation of Cholesterol synthesisCovalent modification

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Regulation of Cholesterol synthesis

• Regulation at transcription

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Lipoprotein metabolism

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CORE

CHOLESTEROLESTERS

TRIGLYCERIDES

MONOLAYER OF PHOSPHOLIPID

AND CHOLESTEROL

INTEGRAL APOPROTEINS

PERIPHERAL APOPROTEINS

Structure of lipoprotein

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Apoproteins

A B C EA-I Liver& intestineA-II Liver

B-48 IntestineB-100 Liver

C-lC-llC-lllAll Liver

Liver

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ClassificationBased on density by ultracentrifugation

i. Chylomicronsii. Very Low Density Lipoproteiniii. Intermediate Density Lipoproteiniv. Low Density Lipoproteinv. High Density Lipoprotein

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Composition and size of lipoprotein

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Lipoprotein function

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Exogenous cycle(Metabolism of CM)

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Endogenous cycle(VLDL)

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HDL- cholestrol metabolismreverse cholesterol transport and

LDL metabolism

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• Regulated: by LDL receptor

• Unregulated : by scavenger receptor(SR)

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Regulated: by LDL receptor

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regulatedLDL uptake byLDL receptor

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Antioxidants Antioxidants Free radicalsFree radicals+-

Scavenger receptorScavenger receptor

Unregulated LDL uptake by scavenger receptor

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Atherosclerosis

• AtherosclerosisAtherosclerosis is a form of is a form of arteriosclerosisarteriosclerosis in which in which thickeningthickening and and hardeninghardening of the vessel of the vessel are caused by are caused by the the accumulation of lipid-laden macrophages or foam accumulation of lipid-laden macrophages or foam cell cell within the arterial wall, which leads to the within the arterial wall, which leads to the formation of a lesion called a plaqueformation of a lesion called a plaque

• Atherosclerosis Atherosclerosis is is not a single disease

• It is the leading contributor to It is the leading contributor to coronary artery coronary artery and and cerebrovascular diseasecerebrovascular disease

Atherosclerosis

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Atherosclerosis

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Hypercholesterolemia

• Normal serum cholesterol level 150-200mg/dl• Increased cholesterol level is seen in following

conditions diabets mellitus, lipid nephrosis, hypothyroidism

• Atherosclerosis• Xanthomas (deposition of cholesterol in

subcutaneous tissue)• Corneal arcus (deposits of lipid in cornea)

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Fredrickson classification of the hyperlipidemias

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Degradation of Cholesterol • Synthesis of bile acids Excretion in the

feces

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Cholesterol-lowering drugs

• Statins• Fibric acid derivatives• Niacin• Bile-acid resins• Cholesterol absorption inhibitors

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Ketone bodies

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Ketone bodies

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

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Acetone

Acetoacetate β-hydroxybutyrate

Ketone bodies importance

• Alternate sources to glucose for energy• Production of ketone bodies under conditions

of cellular energy deprivation• Utilization of ketone bodies by the brain

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ketone bodies production and utilization

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HMG-CoA synthaseHMG-CoA synthase

• By availability of acetyl CoA• Level 1

– Lipolysis

• Level 2– Entry of fatty acid to mitochondria

• Level 3– Oxidation of acetyl CoA

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Diabetic Ketoacidosis

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

Metabolism of complex lipids

Phospholipids• Polar, ionic compounds• alcohol• Phosphodiester bridge• Diacylglycerol or Sphingosine• Types:

– Glycerophospholipids– Sphingophospholipids (sphingosine)

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Synthesis of phospholipids

• Synthesized in smooth endoplasmic reticulum.• Transferred to Golgi apparatus• Move to membranes of organelles or to the

plasma membrane or released out via exocytosis

• All cells except mature erythrocytes can synthesize phospholipids

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Synthesis of Glycerophospholipids

• Biosynthesis of anionic Glycerophospholipids– Phosphatidylglycerol(PG)– Phosphatidylinositol(PI)– Cardiolipin

• Biosynthesis of neutral glycerophospholipids– Phosphatidylcholine(PC)– Phosphatidylethanolamine(PE)

•

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Synthesis of Glycerophospholipids

• First strategy: • biosynthesis of anionic Glycerophospholipids

– CTP:phosphatidate citidyl transferase:

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Alcohol CMP R1

R2

OP

R1

R2

CDP

R1

R2

phosphoalcohol

CTP PPi

Phosphatidate CDP-DAG Phosphatidyl alcohol

Synthesis of Glycerophospholipids

• Second strategy:• Biosynthesis of neutral glycerophospholipids– CTP:phospho alcohol citidyl transferase:

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R1

R2

OH

R1

R2

phosphoalcohol

DAG Phosphatidyl alcohol

Alcohol Phosphoalcohol

CDP-alcohol CMP

Sphingophospholipids

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Sphingomyelin synthesis• Ceramide is required for sphingomyelin synthesis

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PC

DAG

Degradation of glycerophospholipids

• Phospholipases remove one fatty acid from C1 or C2 and form lysophosphoglyceride.

• Lysophospholipases act upon lysophosphoglycerides.– Phospholipase A1– Phospholipase A2– Phospholipase C– Phospholipase D

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Phospholipases

Phospholipse Product Significant

A1 FA--- 1-lysophospholipid Phospholipid transformation

A2 FA--- 2-lysophospholipid Phospholipid transformation, Eicosanoid synthesis

B FA---- Glycerol 3-phosphoalcohol Lysophospholipid degradation

C Phosphoalcohol---1,2DAG Secondary messenger production

D Alcohol---- phosphatidic acid Secondary messenger production

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Degradation of Sphingomyelin

• Sphingomyelinase• Ceramidase• Sphingosine and ceramide act as intracellular

messengers.

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Glycolipids

• Carbohydrate and lipid components• Derivatives of ceramide• Essential components of all membranes,

greatest amount in nerve tissue• Interact with the extracellular environment• No phospholipid but oligo or mono-saccharide

attached to ceramide by O-glycosidic bond.

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Classes of Glycosphingolipids

• Neutral glycosphingolipids :– Cerebrosides– Globosides

• Acidic glycosphingolipids:– Ganglioside– Sulfatides

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Synthesis of Neutral Glycosphingolipids

• Site:– Golgi apparatus

• Subtrates– Ceramide, sugar activated by UDP

• Galactocerobrosides – Ceramide + UDP- galactose

• Glucocerebrosides – Ceramide + UDP – glucose

• Enzymes – Glycosyl transferases

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Synthesis of Acidic Glycosphingolipids

• Gangliosides – ceramide + two or more UDP- sugars react

together to form Globoside.– NANA combines with globoside to form

Ganglioside.

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Synthesis of Acidic Glycosphingolipids

• Sulfatides– galactocerebroside gets a sulphate group from a

sulphate carrier with the help of sulfotransferase and forms a sulfatide.

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Degradation of glycosphingolipids

• Done by lysosomal enzymes

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

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Sphingolipidoses

• Lipid storage diseases• Accumulation of sphingolipids in lysosomes• Partial or total absence of a specific hydrolase• Autosomal 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 prostaglandins

1) Act as local hormones2) Show the autocrine and Paracrine effects3) Are not stored in the body4) Have a very short life span and are destroyed within seconds or few minutes5) Production increases or decreases in response to

diverse stimuli or drugs6) Are very potent in action. Even in minute (ng

concentration), biological effects are observed.

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Synthesis of eicosanoids

• Linoleic 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.

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Synthesis of eicosanoids

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Steroidic anti- inflammation drugs

NSAIDs