Lipids and lipoproteins metabolism

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Lipids and lipoproteins metabolism
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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
• 6. Lipid transport in fed state
• 7. Lipid transport in fasted state
• 8. 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 bodys 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
Atherosclerosis
Obesity
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Lipid metabolism

• 2. Digestion and absorption
• of
• Dietary fats
• in
• GI

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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
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2.3. Digestion of dietary fats

• Digestion in stomach
• Lingual lipase -----acid stable
• Gastric 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
PLase A2
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2.7. Controlof lipid digestion

• Cholecystokinin
• Secretin
• Bicarbonate

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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

• Colipase deficiency

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3. Absorption and secretion of lipids by
enterocytes
TAG triacylglycerol DAG diacylglycerol MAG
monoacylglycerol FA fatty acid CL
cholesterol BS bile salt LPA lysophosphatidate C
E cholestryl ester
ACAT acyl-CoA cholesterol acyl transferase CM
chylomicron MTP microsomal TAG transfer
protein AGPAT 1-acylglycerol-3-phosphate-O-acyltr
ansferase
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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
Glycerol
(exogenous)
Liver
Chylomicron remnant
Clearing factor
HDL
LPL
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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
liver
Small intestine
Acetyl-CoA? FAs TAG
Chylomicron
VLDL
Chylomicron (TAGendo) and VLDL (TAGexo)
Blood stream
Adipose tissue
FAs TAGs
FAs energy
Muscle
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8. Lipids and lipopoteins transport in long
fasted state
Brain
liver
Glucose Glycerol
Ketone bodies Acetyl-CoA energy
FAs Acetyl-CoA Ketone bodies
FAs-albumin
glycerol
Blood stream
ketone bodies
Adipose tissue
FAsGlycerol TAGs
FAs(ketone bodies) energy
Muscle
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• Pathway for catabolism of saturated fatty acids
  at the ß carbon atom with successive removal of
  two carbon atoms as acetyl CoA
• Site
• Cytosol (activation)
• Mitochondria
• Membrane transport
• Matrix ( ß oxidation)

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9.1.1. Activation and transport of fatty acids
into mitochondria
Acyl CoA synthase
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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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The first level
Muscle tissue and liver
The second level
TAG FFA
Glucagon Epinephrine
The third level
Insulin
FFA

-
CAT1
Acetyl-CoA
FFA
-
TCA
NADH
Adipose tissue
Malonyl-CoA
Acetyl-CoA and NADH? inhibition of ? oxidation
enzymes
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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 ( ?
  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
Mitochondria
Cytosol
TCA
Pentose phosphate pathway
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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

Glucagon and epinephrine
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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
Essential fatty acids
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ATP
ADP
NADH, H
NAD
Acyl-CoA
Acyl-CoA
CoA
NADH, H
CoA
NAD
Acyl-CoA
CoA
Pi
Acyl-CoA
CoA
Acyl-CoA
CoA
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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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Lipogenesis
Lipolysis
FFA
Lipolysis
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Mobilization of stored fats and release of FAs
Glucagon epinephrine
P
P
P
P
P
P
HSL
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Metabolism of cholesterol
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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
Cholesterol synthesized in extrahepatic tissues
De novo synthesis
Diet
Liver cholesterol pool
Free cholesterol In bile
Conversion to bile salts/acids
Secretion of HDL and 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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Structure of lipoprotein
INTEGRAL APOPROTEINS
MONOLAYER OF PHOSPHOLIPID AND CHOLESTEROL
CHOLESTEROL ESTERS
CORE
TRIGLYCERIDES
PERIPHERAL APOPROTEINS
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Apoproteins
A B C E
A-I Liver intestine A-II Liver B-48 Intestine B-100 Liver C-l C-ll C-lll All Liver Liver
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Classification

• Based on density by ultracentrifugation
• Chylomicrons
• Very Low Density Lipoprotein
• Intermediate Density Lipoprotein
• Low Density Lipoprotein
• 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 andLDL 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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Unregulated LDL uptake by scavenger receptor
Antioxidants
Free radicals
Scavenger receptor
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Atherosclerosis

• 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 plaque
• Atherosclerosis is not a single disease
• It is the leading contributor to coronary artery
  and cerebrovascular disease

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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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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
HMG-CoA synthase
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• 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
With each ketone body, one hydrogen atom is
released in blood?lowering of pH? Acidosis.
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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
• CTPphosphatidate citidyl transferase

Alcohol CMP
R1
R1
R1
CTP PPi
R2
R2
R2
OP
CDP
phosphoalcohol
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Synthesis of Glycerophospholipids

• Second strategy
• Biosynthesis of neutral glycerophospholipids
• CTPphospho alcohol citidyl transferase

R1
R1
R2
R2
OH
phosphoalcohol
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Sphingophospholipids
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Sphingomyelin synthesis

• Ceramide is required for sphingomyelin synthesis

PC
DAG
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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
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• Eicosanoids- Classification

Eicosanoids are classified in to two main
groups-1) Prostanoids2) Leukotrienes and
LipoxinsProstanoids are further sub classified
in to three groups-a) Prostaglandins(PGs)b)
Prostacyclins(PGIs)c) Thromboxanes (TXs)
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Characteristic features of prostaglandins

• Act as local hormones
• Show the autocrine and Paracrine effects
• Are not stored in the body
• Have a very short life span and are destroyed
  within
• seconds or few minutes
• Production increases or decreases in response to
  diverse stimuli or drugs
• 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
NSAIDs
Steroidic anti- inflammation drugs