Null 2

m.ubaidullah1030@kemu.edu.
pk 03130580487
Muhammad Ubaidullah Arshad
Final year MBBS KEMU
m.ubaidullah1030@kemu.edu.pk
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m.ubaidullah1030@kemu.edu.pk 03130580487
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Muhammad
Ubaidullah Arshad
LIPIDS
METABOLISM OF

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CONTENTS
Sr.No Title Page No
1 Synthesis & Regulation of Fatty Acids 7-24

Ubaidullah Arshad
2 Oxidation of Fatty Acids: types and its regulation 25-43
3 Synthesis, Storage, Mobilization & Regulation of TAG 44-51
4 Synthesis & Regulation of Ketone Bodies 52-58
Muhammad
5 Synthesis & Regulation of Cholesterol 59-71

6 Synthesis & Regulation of Bile acid and Bile salts 72-82
7 Metabolism of Lipoproteins 83-109
8 Synthesis of Phospholipids, Glycosphingolipids and Eicosanoids 110-132

Metabolism
9 Fatty liver disease 133-142
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CONTENTS
• Denovo Synthesis of Fatty Acids

• Regulation of Fatty Acid Synthesis
• Elongation of Fatty Acid
Synthesis & • Desaturation of Fatty Acids Side chains
Regulation
of Fatty
Acids
DE NOVO Synthesis of Fatty Acids
• De novo synthesis refers to the synthesis of complex molecules from simple
molecules such as sugars or amino acids, as opposed to recycling after partial
degradation
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De novo synthesis of Fatty acids
De novo synthesis of Purines
• Site
1. Organ Level
Liver, Lactating Mammary Glands and, to lesser extent in adipose tissue
2. Cellular Level
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Cytosol

• Precursors
1. Acetyl CoA 4. Mn+2
2. ATP 5. HCO3− (as a source of CO2)
3. NADPH
• Sources of Precursors
1. Electron Transport Chain
2. Glycolysis
3. TCA Cycle
4.
5.
HMP Shunt Pathway
NADP+ Dependent Malate Dehydrogenase 9
STEPS OF SYNTHESIS
Ubaidullah Arshad
Synthesis occurs in following steps
1. Conversion of Glucose to Cytosolic Acetyl CoA
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2. Conversion of Acetyl CoA to Malonyl CoA

3. Synthesis of Fatty Acids by Fatty Acid Synthase Complex
4. Elongation of Fatty Acids
5. Desaturation of Fatty Acids
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STEP1=Production of Cytosolic Acetyl CoA
• Transfer of Mitochondrial Acetate units
formed by TCA cycle and by certain amino
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acids to Cytosol
• No Transporter Available for CoA, so
Transport occurs in the form of Citrate
• Energy in the form of ATP is required
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• One ATP per Acetyl CoA is required

• Cytosolic Acetyl CoA is viewed as high
energy signal
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STEP2=Conversion of Acetyl CoA to
Malonyl CoA
• Energy for carbon-to carbon condensation is supplied by the process of
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carboxylation followed by decarboxylation
• Acetyl CoA is carboxylate to Malonyl CoA
• One ATP is used
• Rate Limiting and regulated step
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• Enzyme involved

 Acetyl CoA Carboxylase
 Requirements
1. ATP
2. CO2
 Coenzymes
1. Biotin
 Regulation
 Short term regulation
 Long term regulation 12
Mechanism of Action of Acetyl CoA
Carboxylase
Domains
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1. Biotin Carboxylase
2. Transcarboxylase
3. Biotin Carrier protein
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Regulation of Acetyl CoA Carboxylase
• It occurs by two ways
1. Short-Term Regulation
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a) Allosterically
 Allosteric activation by citrate
Causes protomers which are non-functional to polymerize and form
functional enzyme
 Allosteric inactivation by long-chain fatty acyl CoA
Causes depolymerization and thus deactivation
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b) Covalently

 AMPK phosphorylates and inactivates ACC
 AMPK is itself allosterically activated by AMP and covalently by
phosphorylation
 In Prescence of Glucagon the ACC is phosphorylated and thus inactivated
2. Long-Term Regulation
 Prolonged consumption of high caloric low fat diet results in
increased synthesis of ACC
 Low caloric high fat diet decreases the synthesis of ACC
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STEP3=Fatty Acid synthase Complex
• The remaining steps are catalyzed
by multifunctional, dimeric enzyme
i.e. Fatty acid Synthase (FAS)
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• Each FAS monomer is a

multicatalytic polypeptide with
seven different enzyme domains
plus a domain that covalently bind a
molecule of 4-Phosphopantetheine
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Reaction Steps
1. Acetyl group is transferred from Acetyl CoA to –SH group of ACP by
Acetyl CoA-ACP Acetyltransacylase
2. The two-carbon fragment is transferred to temporary holding site,
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thiol group of cysteine residue of enzyme
3. Vacant ACP accepts a three-carbon Malonyl group from Malonyl CoA
by Malonyl CoA-ACP Transacylase
4. The acetyl group on the cysteine residue condenses with malonyl
group on ACP and CO2 is released. This results in 4 carbon unit
attached to ACP domain by 3-Ketoacyl-ACP-Synthase
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The keto group is reduced to an alcohol by 3-Ketoacyl ACP

5.
reductase. NADPH is used
6. A molecule of water is removed creating double bond between
carbon 2 and 3 by 3-Hydroxyacyl ACP dehydratase. NADPH is
used
7. The double bond is reduced by Enoyl-ACP reductase
8. Repetition of steps
9. Release of Palmitate by Thioesterase
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NET EQUATION
Palmitate +8 CoA +7 ADP +7 Pi + 6H2O

8 Acetyl CoA+ 7 ATP + 14 NADPH +14H

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Regulation of Fatty Acid synthesis
• It occurs by
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1. Acetyl CoA Carboxylase

2. Hormonal influence
3. Dietary Regulation
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4. Availability of NADPH

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ELONGATION OF FATTY ACIDS
Ubaidullah Arshad
• Palmitate (16;0) is the product of Fatty

acid Synthesis
•
Further elongation by addition of 2-
carbon fragment occurs in Smooth
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Endoplasmic Reticulum SER

• Elongation requires separate set of
enzymes
• Occurs in brain
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•
•
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Ubaidullah Arshad
Occurs in SER
O2, NADH, Cytochrome b5 and FAD is required
DESATURATION OF FATTY ACIDS

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Self-Assessment
Ubaidullah Arshad
• Explain the net equation for synthesis of Palmitate from Acetyl CoA
• Omega end of every fatty acid comes from the starting first Acetyl CoA.
Explain
• What is the functional Significance of Fatty Acid Synthase Complex?
Muhammad
• Explain how Metformin lowers serum TAG

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CONTENTS
• β oxidation of Fatty Acids

• α oxidation of Fatty Acid
• ω-oxidation of Fatty Acid
Oxidation
of Fatty
Acids
β-OXIDATION OF FATTY ACIDS
• Major pathway for catabolism of Fatty Acids
• Pathway for Energy Generation

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• Site
Mitochondria
• At each step two-carbon fragments are successively removed from
carboxyl end of the fatty acyl CoA producing Acetyl CoA, NADH and
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FADH2

• Steps
1. Transport of long-chain fatty acyl CoA into Mitochondria by
Carnitine
2. Transport of Short and medium- chain fatty acids into Mitochondria
3. 4 Steps of Beta-Oxidation w
4. Repetition of these 4 steps till complete generation of Energy
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Transport of Long chain fatty acids into
Mitochondria
 LCFA in the cytosol are converted to CoA derivative by Long-
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chain fatty acyl CoA Synthetase/thiokinase. Located in outer
mitochondrial membrane. 2ATP are used
 They cannot be transported across inner-mitochondrial
membrane so converted into Carnitine which carries them
across the membrane
1. Acyl group is transferred from CoA to carnitine-by-Carnitine
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palmitoyl transferase 1 (CPT-1). Located in outer

mitochondrial membrane

2. Acylcarnitine is transported into mitochondrial matrix
3. Carnitine palmitoyl transferase II (CPT-II) located in
inner mitochondrial membrane catalyzes transfer of the
acyl group from carnitine to CoA in the mitochondrial matrix
generating free carnitine
 Inhibitor
Malonyl CoA inhibits CPT-I thus preventing the entry of Long chain-
acyl groups into mitochondrial
Increased Acetyl CoA/ CoA ratio decreases CoA requiring thiolase
reaction 27
Transport of Short & Medium chain fatty
acids into Mitochondria
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• Fatty acids shorter than 12 carbons can cross the inner mitochondrial
membrane
• They do not require carnitine shuttle
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• Not regulated by CPT-1

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4 STEPS OF β-OXIDATION
• Sequence of 4 reactions results in the shortening of
fatty-acids by two carbons from the carboxyl end
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• Each step is catalyzed by enzyme of chain length
specificity
1. Oxidation producing FADH2
2. Hydration
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3. Oxidation producing NADH

4. Thiolytic cleavage releasing Acetyl CoA
• For even number fatty acids numbers of cycle =

N/2-1 Where N= Number of Carbon Atoms
• Acetyl CoA can undergo Ketogenesis of TCA cycle
• NADH and FADH2 thus produced can generate
energy by ETC
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NET ENERGY GENERATION
• Activation of a fatty acid requires:
2 ATP
Ubaidullah Arshad
• One cycle of oxidation of a fatty acid produces: NET ATP PRODUCTION BY

1 NADH= 2.5 ATP PALMITATE = 106 ATP
1 FADH2 = 1.5 ATP
• Acetyl CoA entering the citric acid cycle produces:
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1 Acetyl CoA =10 ATP

Overall reaction of β-Oxidation of palmitoyl
CoA (fatty acid) :
Palmitoyl CoA + 7 FAD + 7 NAD+ + 7CoA + 7H2O
8 acetyl Co A + 7 FADH2 + NADH+7H+
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OXIDATION OF ODD-CHAIN FATTY
ACIDS
Ubaidullah Arshad
• This process proceeds by same reaction steps as that of
fatty acids with even number of carbons until the final 3
carbons are reached i-e Propionyl CoA
• Propionyl CoA is then converted into D-Methylmalonyl
CoA
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• D-Methylmalonyl CoA is converted to L-Methylmalonyl

CoA

• L-Methylmalonyl CoA is converted into Succinyl CoA
which enters in the TCA cycle
• Methylmalonic acidemia results from Vitamin B12

deficiency
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β OXIDATION OF UNSATURATED
FATTY ACIDS
• Provides less energy
Ubaidullah Arshad
• Oxidation of Monounsaturated fatty acids require

additional one enzyme 3,2-enoyl CoA isomerase
converts 3-cis derivative to 2-trans derivative
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• Oxidation of Polyunsaturated fatty acids require

additional two enzymes 3,2-enoyl CoA
isomerase and NADPH-Dependent 2,4-dienoyl
CoA reductase
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β OXIDATION OF FATTY ACIDS IN
PEROXISOMES
Ubaidullah Arshad
• Very-long chain fatty acids having carbons more

than 22 are oxidized by Beta-oxidation in
peroxisomes
• Primary site of synthetases that activate fatty
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acids of this length

• Initial dehydrogenation is catalyzed by FAD-
containing acyl CoA oxidase. The FADH2
produced is oxidized by molecular oxygen which
is reduced to H2O2.Therefore no ATP generated
• The H2O2 is reduced to H20 by Catalase
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Self-Assessment
Ubaidullah Arshad
• Calculate net energy production by one mole of Mysteric Acid

• What are the sources of Carnitines in diet
• Enlist Monounsaturated and Polyunsaturated Fatty Acids
• Enlist very-Long Chain Fatty Acids
Muhammad

• Compare and contrast Beta oxidation in peroxisome and mitochondrion
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α-OXIDATION OF FATTY ACIDS
• Occurs in Peroxisomes
• Occurs for Branched chain Phytanic Acid which is a product of

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chlorophyll metabolism
• Not a substrate for Acyl CoA dehydrogenase because of methyl-

group on its Beta-Carbon
• Hydroxylated on Alpha-Carbon by phytanoyl CoA-alpha-
hydroxylase
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• The resultant products undergoes Beta-Oxidation

• REFSUM DISEASE
 Rare autosomal recessive disorder caused by deficiency of phytanoyl
CoA-alpha-hydroxylase
 Results in accumulation of phytanic acid in plasma and tissues
 Symptoms are mainly neurological
 Treatment involves dietary restriction
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ω-Oxidation of Fatty Acid
Ubaidullah Arshad
• Minor pathway occurs in Endoplasmic

reticulum
• Generates Di-Carboxylic Acids
• Its upregulation is seen in MCAD Deficiency
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CONTENTS
• Carnitine Deficiencies
• MCAD Deficiency
DISORDERS OF • X-Linked ALD & Zellweger Syndrome
Oxidation • Refsum Disease
of Fatty
Acids
Carnitine Deficiencies
• Primary Carnitine Deficiency

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 Defect in membrane transporter for carnitine in skeletal and cardiac muscle and
kidney
 Treatment included carnitine supplementation
• Secondary Carnitine Deficiency
 Results from defect in Beta-Oxidation
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 Leads to accumulation of Acyl carnitines that are excreted in urine decreasing the

availability
• Acquired Carnitine Deficiencies

 Seen in liver disease i.e., Decreased synthesis of Carnitine
 Those taking Anti-seizure drugs i.e., decreases renal reabsorption
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CPT-Deficiencies
Ubaidullah Arshad
• CPT-I Deficiency
 Affects Liver
 Inability to use LCFs for fuel greatly impairs tissue ability to synthesize glucose
during fast
 Leads to severe hypoglycemia, coma and death
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• CPT-II Deficiency


Affect Liver, Skeletal and Cardiac Muscle
 Mostly affects the skeletal muscles
 Presents as Muscle weakness with myoglobinuria following prolonged exercise
 Treatment is avoidance of fasting and adopting a diet high in carbohydrates and low
fat but supplemented with medium chain TAGs
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MCAD Deficiency
• Autosomal Recessive
• Most common Inborn –Error of Metabolism
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• Most common error of fatty acid oxidation

• MCAD deficiency results in decreased ability to oxidize medium
chain fatty acids.(C=4-10)
• Hypoglycemia with hypo-ketonemia its diagnostic feature
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• Cause of SIDS and Reye Syndrome

• Dicarboxylic acids are secreted in
urine
• Treatment is avoidance of fasting
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X-Linked ALD & Zellweger Syndrome
• X-Linked ALD
 Deficiency of Adrenoleukodystrophic protein
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 Involved in transport of VLCFs to inside to peroxisomes
 Leads to accumulation of VLCFs and symptoms
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• Zellweger Syndrome

 Also called as Cerebrohepatorenal Syndrome
 Results from absence of Peroxisomes
 VLCFs cannot be oxidized
 Mainly affects brain, liver and kidney
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Self-Assessment
Ubaidullah Arshad
• Enlist Distinctive Head and Neck Features of Zellweger Syndrome

• Differentiate between Alpha and Omega Oxidation
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CONTENTS
• Synthesis of TAG
• Triacylglycerol cycle
• Storage of TAG
SYNTHESIS, • Mobilization of TAG
•
STORAGE , •
Regulation of TAG Metabolism
Glyceroneogenesis
MOBILZATION
& REGULTAION
OF TAG
SYNTHESIS OF TAG
• Glycerol-3-Phosphate is the initial acceptor of fatty acids during
TAG synthesis. There are two pathways for its production
1. In both liver and Adipose tissues, it can be produced from
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glucose via glycolytic pathway

2. Second pathway occurs in liver only uses glycerol kinase to
convert glycerol to glycerol phosphate using ATP
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SYNTHESIS OF TAG
• Fatty acid must be

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first activated to CoA
derivative
• Four reactions are
involved further
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Muhammad
Ubaidullah Arshad
TAG CYCLE

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STORAGE OF TAG
• Stored mostly in the White Adipose Tissue
• Very little is stored in liver
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Muhammad

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Muhammad
Ubaidullah Arshad
ATGL
MOBILIZATION OF TAG
HSL
MAG

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Muhammad
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REGULATION OF TAG

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Fate of Glycerol and Fatty Acids
• GLYCEROL
• Transported to the liver through blood where it is phosphorylated and
participates in TAG synthesis
• Can undergoes glycolysis or Gluconeogenesis
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• FATTY ACIDS
• The free unesterified moves through the cell membrane of adipocyte and
bind to plasma albumin and transported to various tissues and to liver for
oxidation
• Over 50% fatty acids released by White adipose tissue are re-esterified to
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Glycerol-3-Phosphate through glyceroneogenesis as it lacks Glycerol

Kinase
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CONTENTS
• Synthesis of Ketone Bodies

• Regulation of Synthesis of Ketone Bodies
• Ketolysis
KETOGENESIS • Type 1 Diabetes & Ketoacidosis
& Its • Test for Biochemical Detection of Ketone
Bodies
REGULATION
KETOGENESIS
• Site
Mitochondria
• Precursor
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Acetyl CoA
• Ketone Bodies
β-Hydroxybutyrate
Acetoacetate
Acetone
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• Importance

Ketone bodies are important sources of energy for the peripheral tissues because
1. They are soluble in aqueous solution and, therefore, do not need to be incorporated into lipoproteins or carried by
albumin as do the other lipids;
2. They are produced in the liver during periods when the amount of acetyl CoA present exceeds the oxidative capacity of
the liver;
3. They are used in proportion to their concentration in the blood by extrahepatic tissues, such as the skeletal and cardiac
muscle, intestinal mucosa, and renal cortex. Even the brain can use ketone bodies to help meet its energy needs if the
blood levels rise sufficiently.
Thus, ketone bodies spare glucose, which is particularly important during prolonged periods of fasting 53
STEPS OF KETOGENESIS
• Occurs in Liver during Fasting
Ubaidullah Arshad
• STEPS
1. Mobilization of Fatty Acids from Adipose tissue
2. β-Oxidation generating Acetyl CoA
3. Formation of Acetoacetyl CoA
4. Synthesis of 3-hydroxy-3-methylglutaryl coenzyme A
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HMG CoA synthase is the rate-limiting step

1. Synthesis of the ketone bodies
HMG CoA is cleaved by HMG CoA lyase to produce acetoacetate and acetyl CoA
Acetoacetate can be reduced to form 3-hydroxybutyrate with NADH as the
hydrogen donor. Regulated by NADH/NAD+ ratio
Acetoacetate can also spontaneously decarboxylate in the blood to form acetone
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REGULATION
Ketogenesis is regulated at three crucial steps
1. The factors regulating mobilization of FFA from adipose tissue

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are important in controlling ketogenesis
2. There is regulation of entry of fatty acids into the oxidative
pathway by carnitine palmitoyl transferase-I (CPT-I)
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3. The partition of acetyl-CoA between the ketogenic pathway and
the pathway of oxidation to CO2 is regulated so that the total free
energy captured in ATP which results from the oxidation of FFA
remains constant as their concentration in the serum changes.
NADH/NAD+ ratio
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KETOLYSIS
Ubaidullah Arshad
Muhammad

Extrahepatic tissues, including the brain but excluding cells
lacking mitochondria (for example, RBCs), efficiently oxidize
acetoacetate and 3-hydroxybutyrate in this manner. In contrast,
although the liver actively produces ketone bodies, it lacks Thiophorase
Thiophorase and, therefore, is unable to use ketone bodies as
fuel.
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Type 1 Diabetes and Ketoacidosis
Can occur in Type 1 Diabetes , Prolonged Fasting and Ethanol
consumption
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Diabetic Ketoacidosis
In uncontrolled Diabetes
• There is severe ketosis
• Urinary excretion of ketone bodies may be as high as
5,000mg/24 hour
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• Blood concentration may reach 90mg/dl

• Frequent symptom is fruity odor due to acetone production
• Rothera Test in urine is positive
• Elevation of ketone bodies in blood results in acidemia
called as Metabolic Acidosis
• Urinary loss of glucose and ketone bodies results in
dehydration
• This results in the coma state called as Diabetic
Ketoacidotic Coma DKC
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Self-Assessment
Ubaidullah Arshad
• How will you Differentiate Between DKC and HONKC? Give biochemical
basis of both
• What are ketogenic diet? Why are they recommended ?
• Why children are more prone to ketosis?
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CONTENTS
• Synthesis of Cholesterol
• Regulation of Synthesis of Cholesterol
• Degradation of cholesterol
Cholesterol
synthesis &
Its
REGULATION
Synthesis of Cholesterol
• Synthesized by virtually all the tissues of the body
• Normal levels are < 200mg/dL
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• Its an endergonic process

• Subcellular site
 Cytosol
 Membrane of SER
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• Precursors

 Acetyl CoA
 NADPH
• STEPS
1. Synthesis of HMG CoA
2. Synthesis of Mevalonate
3. De novo Synthesis of Cholesterol 60
STEP 1= Synthesis of HMG CoA
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• 3 Acetyl CoA are utilized

• HMG-CoA synthase has two isoenzymes in Liver
1. Cytosolic one involved in synthesis of Cholesterol
2. Mitochondrial one involved in synthesis of ketone bodies
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STEP 2= Synthesis of Mevalonate
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• Reduction step
• Rate Limiting and Regulated Step
• Irreversible step
• 2 molecules of NADPH are utilized
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• HMG-CoA Reductase is integral membrane protein of ER with

its catalytic domain in the cytosol
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Mevalonate To Lanosterol

63
Ubaidullah Arshad
• 18 ATPs are required to make

Squalene
• Six Isoprenoid Units are used
• Prenylation ?
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• Squalene is converted into Sterol Lanosterol by sequence of

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reactions catalyzed by ER-associated enzymes that use

Oxygen and NADPH
• The hydroxylation of linear sequence triggers the cyclization
of the structure to lanosterol
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Lanosterol To Cholesterol
Multi-step process involves ER
enzymes
1. Reduction of Carbon number
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from 30 to 27
2. Removal of Methyl group from
C14 and C4
3. Shift of double bond from C8 to
C5
4. Reduction of double bond
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present between C24 and C25

Smith-Lemli-Optiz Syndrome
• Autosomal Recessive
• Partial Deficiency of 7-
dehydrocholesterol-7-
reductase
• Associated with vitamin D
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deficiency
Regulation of Cholesterol Synthesis
• HMG-CoA reductase is the major control point it is subject to different
kinds of metabolic control
1. Sterol-Dependent Regulation of Gene Expression

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 Transcription factor SREBP-2 controls the expression

of gene
 Normally present in the ER membrane and bound to SCAP
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 When Sterol is low the SREBP-2 is released and

binds to the cis-acting SRE on the DNA

 Binding Causes increased transcription of enzyme
 When sterol is high it binds to the sterol sensing domain
of SCAP and causes its binding to INSIG causing
retention
HMG-CoA
Reductase 67
2. Sterol-Accelerated enzyme destruction
When sterol is high it binds to sterol sensing domain of the
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reductase enzyme leading to binding to insig. Binding leads to

ubiquitination and proteasomal degradation
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3. Hormonal Regulation

Thyroxine and Insulin
upregulates
Glucagon and
Glucocorticoids inhibits
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4. Sterol-Independent Phosphorylation/Dephosphorylation
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Muhammad

5. Inhibition by drugs
Statin drugs competitively inhibit the
enzyme HMG-CoA reductase
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Degradation of Cholesterol
• Humans
 Ring structure cannot be metabolized to CO2 and H2O
 Intact sterol is eliminated by conversion to
Ubaidullah Arshad
1. Bile acids
2. Bile salts
 A small percentage in excreted in feces and by secretion of cholesterol
into the bile
 Some cholesterol is modified by bacterial in the intestine to
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Coprostanol and Cholestanol

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Self-Assessment
Ubaidullah Arshad
• Enlist some statin drugs

• What is prenylation? Give its importance
• Illustrate the transcriptional control of Cholesterol Biosynthesis
Muhammad
• Give total amount of Acetyl CoA, ATP and NAPDH used for the synthesis of
one mole of Cholesterol

• How many CO2 are produced per Squalene
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CONTENTS
• Synthesis of Bile Acids

• Regulation of Synthesis of Bile Acids
• Enterohepatic Circulation of Bile Acids
synthesis & • Bile Acid Sequestrants
REGULATION • Cholelithiasis
of bile acids
Synthesis of Bile Acids
• Synthesis is multistep-multi organelle pathway in which
1. Hydroxyl groups are added on specific position on the steroid structure
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2. The double bond of cholesterol ring is reduced
3. The hydrocarbon chain is shortened by 3 carbons
4. Carboxyl group is introduced at the end
• Site
Liver
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• Precursor

Cholesterol
• Primary Bile Acids

Cholic Acid & Chenodeoxycholic Acid
• Secondary Bile Acids

Deoxycholic Acid & Lithocholic Acid
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STEPS of Synthesis of Bile Acids
• First step is Rate Limiting and Regulated Step
• 7-α-Hydroxylase is ER- Associated CYP-450 enzymes
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• Enzyme is present only in Liver
• Expression of Enzyme is Down-regulated by
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Bile Acids
- Bile Acids

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Muhammad
Ubaidullah Arshad
STEPS of Synthesis of Bile Acids

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Synthesis of Conjugated Bile Acids
• Conjugated with either taurine or Glycine
• Conjugation is by Amide bond between the
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carboxyl-end of bile acids and amino group

of added compound
• Energy in the form of ATP is required
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• Importance

1. Addition of Glycine or taurine results in the
Prescence of carboxyl group with a pKa or
a sulfate group, both of which are fully
ionized at the alkaline pH of Bile
2. The conjugated, ionized bile acids/salts are
more effective detergents than
unconjugated ones
3. The amphipathic nature is thus enhanced
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Synthesis of Secondary Bile Acids
• Bacteria in the intestine can Deconjugate and
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Dehydroxylate at carbon 7 producing Secondary Bile
Acids/Salts
• Deoxycholic Acid is produced from Cholic Acid
• Lithocholic Acid is produced from Chenodeoxycholic Acid
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Entero-Hepatic Circulation of Bile Acids
The continuous process of secretion of bile salts into the bile,
their passage through the duodenum where some are
deconjugated then dehydroxylated to secondary bile salts,
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their uptake in the ileum, and subsequent return to liver as a
mixture of primary and secondary forms is termed as
Entero-Hepatic Circulation
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Bile Acid Sequestrants
• They bind bile salts in the gut, prevent their reabsorption , so
promote their excretion
• Used for the treatment of Hypercholesterolemia because of
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removal of negative influence on 7-alpha-hydroxylase

enzyme
• Thus, allowing more conversion of Cholesterol to Bile Acids
and thus excretion from the body `
• E.g. Cholestyramine
Muhammad

79
Cholelithiasis
• Formation of Stones within the Gall- Bladder
• Common in Fat Female Fertile of Forty
Ubaidullah Arshad
• BIOCHEMICAL BASIS
• Cholesterol coming into the bile for excretion
is remained solubilized by the Bile salts and
Phosphatidylcholine
Muhammad
• If there is their deficiency or excess of

cholesterol in excreted the cholesterol may
precipitate in the gall bladder leading to
Cholelithiasis
• It also results from increased secretion of
cholesterol into the bile using fibrates
• USG Abdomen
• Laparoscopic Cholecystectomy for their removal
80
Muhammad
Ubaidullah Arshad

81
Self-Assessment
Ubaidullah Arshad
• Give the mechanism of action and use of Bile Acid Sequestrants.

• Enlist Precipitating Factors for formation of Gall stones.
• Enlist types of Gall stones. What are the major ones?
Muhammad
• Illustrate the regulatory step of Bile Acid Synthesis

• Illustrate Entero-Hepatic Circulation of Bile Acids
• Diagnostic Investigation for detection of Gall stones is?
• Latest Surgical procedure and Treatment of Choice for Removal of Gall Stones
from body is ?
82
CONTENTS
• Lipoproteins and types

• Metabolism of Chylomicrons
• Metabolism of VLDL
• Metabolism of LDL
•
Metabolism •
Metabolism of HDL
Hyperlipidemias
of • Role of Lipoprotein(a) in heart disease
LIPOPROTEINS
LIPOPROTEINS
• They are the spherical macromolecular complexes of lipids
and specific proteins called as apolipoproteins
Ubaidullah Arshad
• Types
They differ in lipid and protein composition , size, density
and site of origin;
1. Chylomicrons
2. Very-low density lipoproteins VLDL
Muhammad
3. Intermediate-Density Lipoprotein IDL

4. Low- density Lipoproteins LDL
5. High Density Lipoproteins HDL
• Composition
• TAG
• Protein
• Phospholipids
• Cholesterol
• Cholesteroll esters 84
Ubaidullah Arshad
Muhammad

Total Cholesterol (C) mg/dl = LDL (C) +HDL (C)+ VLDL (C)
Where as VLDL (C) = TAG/5 because TAG represent 20% of volume of VLDL
Called as Friedewald formula 85

Apolipoproteins
• The apolipoproteins associated with lipoprotein particles have
several diverse functions
• Providing recognition sites for cell surface receptors
Ubaidullah Arshad
• Serving as activators and coenzymes
• Some are essential structural component
• Whereas others can be freely transferred between
lipoproteins
• Divided by structure and function in several major classes
each having subclasses
Muhammad

86
Metabolism of Chylomicrons
• They are assembled in the intestinal mucosa and carry
dietary(exogenous) TAG, Cholesterol, fat soluble vitamins and
cholesteryl esters to peripheral tissues. Contain 90% TAG
Ubaidullah Arshad
• STEPS
1. Synthesis of Apolipoproteins in RER
2. Assembly of chylomicrons SER by MTP (Microsomal
Triglyceride transfer protein)
Muhammad
3. Translocation to Golgi to form secretory vesicle

4. Modification of nascent chylomicron particle

5. Degradation of TAG by Lipoprotein Lipase
6. Formation of Chylomicron remanent
87
Ubaidullah Arshad
Insulin upregulates the enzyme
in adipose tissue and decreases
in muscle Enzyme activity regulated
Muhammad
by hormonal and
nutritional status

88
Metabolism of VLDL
• VLDL are produced in
liver
Ubaidullah Arshad
• Contain endogenously
TAG 60%
• STEPS
1. Release from liver
Muhammad
2. Modification in
Circulation

• Transfer of
Apolipoprotein
to HDL
• Transfer of
TAG to HDL
3. Conversion to Low
density Lipoproteins
89
Self-Assessment
Ubaidullah Arshad
• What do you know the link between Apolipoprotein E and Alzheimer's Disease ?
• Draw general structure of Lipoprotein particle
• Illustrate the electrophoretic pattern of Lipoproteins.
Muhammad

90
Metabolism of LDL
• LDL contains 50% Cholesterol and
cholesteryl esters, 22 % phospholipids,
20% proteins 8 % TAG
Ubaidullah Arshad
• STEPS
1. Receptor Mediated Endocytosis
2. Effect of endocytosed
Muhammad
cholesterol on cellular

Cholesterol levels
91
Metabolism of LDL
1. Receptors are apoE/apoB100
2. LDL receptors are negatively charged
Ubaidullah Arshad
glycoprotein that are clustered in pits
on the cell membrane. On Cytosolic
side they are stabilized by Clathrin
3. After binding Endocytosis occurs
4. The vesicle containing LDL loses its
CURL
clathrin coat and fuses with other same
Muhammad
vesicle forming endosomes

5. The Ph of endosome falls allows
separation of LDL from its receptor
6. The receptor are recycled
7. Lipoprotein transferred to lysosomes
and degradation by lysosomal acid
hydrolase releasing free cholesterol,
amino acids, fatty acids and
phospholipids
92
Metabolism of LDL
• Lipoprotein derived cholesterol affects
the cellular cholesterol in several ways
Ubaidullah Arshad
1. Expression of gene for HMG CoA

reductase is inhibited by high
cholesterol
2. Synthesis of new receptor is reduced
by decreasing expression of LDL CURL
Muhammad
receptor gene

3. If cholesterol is not required
immediately it is esterified by acyl
CoA:cholesterol acyltransferase
(ACAT) forming cholesteryl ester
that is then stored
93
Metabolism of LDL
• Familial Hypercholesterolemia
• Deficiency of functional LDL receptor
Ubaidullah Arshad
• Autosomal Dominant Hypercholesterolemia

• Increased activity of protease proprotein
convertase subtilisin/kexin type 9 (PCSK9)
• It promotes the degradation of the receptors
It promotes the defects in apo-B100 CURL
Muhammad

• Niemann-Pick Disaease Type C
• Storage disease caused by inability to
transport free cholesterol out of the
lysosome
• Late-Onset Wolman Disease

• Storage disease caused by inability to
hydrolyze cholesteryl esters in lysosomes
94
Role of oxLDL in Plaque Formation
• Not regulated
Ubaidullah Arshad
• Mediated by Scavenger
receptors class A (SRA)
• Mediated through
macrophages
Muhammad

• Cholesteryl esters
accumulate forming the
foam cells which leads to
formation of Plaque
95
Muhammad
Ubaidullah Arshad
Role of oxLDL in Plaque Formation

96
Metabolism of HDL
• HDL contains Apo-A1
• Functions of HDL
Ubaidullah Arshad
1. Supply of Apolipoprotein
Apo CII
Apo E
2. Uptake of unesterified
cholesterol from tissues
Muhammad

3. Esterification of
Cholesterol
By plasma enzyme
LCAT (Apo-A1)
97
Metabolism of HDL
Reverse Cholesterol Transport
• The selective transport of cholesterol from peripheral cells to HDL, from HDL to liver for bile
acid synthesis or disposal via bile and to steroidogenic cells for hormone synthesis is called as
Ubaidullah Arshad
Reverse cholesterol transport

• This is basis for inverse relationship between plasma HDL concentration and atherosclerosis
• The efflux from peripheral tissues is mediated by ABCA1 (ATP-Binding Cassette protein 1)
• Uptake in liver is
Muhammad
mediated through the

Scavenger receptor
class B Type 1 SR-B1
98
Role of Lipoprotein (a) in Heart Disease
Ubaidullah Arshad
• Lipoprotein (a) is associated with increased risk for coronary heart disease
• Lp (a) is identical in structure to an LDL particle with additional presence of apo (a) that is covalently
Muhammad
linked to single site of Apo-B100

• Trans-fatty acid increase its levels in body where as Omega-3 fatty acids, Niacin decreases
• BIOCHEMICAL BASIS
Apo (a) is structurally homologous to plasminogen which is a precursor of blood protease whose
target is fibrin, the main component of blood clots
It is hypothesized that elevated Lp (a) shows the breakdown of clots that trigger heart attacks
because it competes with plasminogen for binding to fibrin
99
Muhammad
Ubaidullah Arshad

100
LIPIDS PROFILE
Panel of blood tests that serves as an initial broad
medical screening tool for abnormalities in
Ubaidullah Arshad
lipids , such as cholesterol and triglycerides.
The lipid profile typically includes:

• Low-density lipoprotein (LDL)
• High-density lipoprotein (HDL)
Muhammad
• Triglycerides
• Total cholesterol

Assessment of Lipoproteins
This can be done by the following
methods:
1. Overnight FASTING plasma appearance
2. Electrophoresis
3. Ultra-centrifugation
101
Muhammad
Ubaidullah Arshad
LIPIDS PROFILE

102
Muhammad
Ubaidullah Arshad Hyperlipidemia
Fredrickson Classification of

103
Muhammad
Ubaidullah Arshad
LIPIDS PROFILE

104
Muhammad
Ubaidullah Arshad
LIPIDS PROFILE

105
Muhammad
Ubaidullah Arshad
LIPIDS PROFILE

106
Muhammad
Ubaidullah Arshad
LIPIDS PROFILE

107
Tangiers Disease
• Familial Alpha lipoprotein deficiency
• Due to mutation of ABCA1 gene
Ubaidullah Arshad
• HDL particles are absent because of increased degradation

• Reverse transport is severely affected leading to accumulation of
cholesteryl esters in tissues
• TAG are elevated and results in increased risk of atherosclerosis
Muhammad

Sign and Symptoms
• Enlarged orange tonsils
• Hepatosplenomegaly
• Peripheral neuropathy
• Clouding of cornea
108
Self-Assessment
• How smoking leads to atherosclerosis. Give Biochemical basis of this
• What is Metabolic Syndrome
Ubaidullah Arshad
• Explain Reverse Cholesterol Transport

• Tabulate hyperlipidemias with their appearance
• What are pre-requisites for Lipid Profile.
Muhammad
• Enlist Hypolipoproteinemia's

• Give Diagnosis
109
CONTENTS
• Synthesis of Phospholipids
• Synthesis of Glycerol ether Phospholipids
• Degradation of Phospholipids
Phospholipids, • Deficiency of Lung Surfactant
•
glycosphingo •
Metabolism of Glycolipids
Degradation of Sphingolipids
lipids and • Sphingolipidosis
eicosanoid
metabolism
Muhammad
Ubaidullah Arshad

111
Synthesis of Phospholipids
Synthesis involves two strategies
Ubaidullah Arshad
1. Either the donation of PA from
CDP-DAG to alcohol
2. Or Donation of Phosphomonoester
of alcohol from CDP-alcohol to
1,2-Diacylglycerol
Muhammad

In both cases CDP-bound structure is
considered an “Activated
intermediate” and CMP is released as a
side product
112
Muhammad
Ubaidullah Arshad

113
Muhammad
Ubaidullah Arshad
role in membrane
Phosphatidylserine has
synthesis and apoptosis


114
Muhammad
Ubaidullah Arshad

115
Muhammad
Ubaidullah Arshad

116
Muhammad
Ubaidullah Arshad Surfactant
Role of Phosphatidylcholine in Lung

117
Muhammad
Ubaidullah Arshad Signaling Gq Protein
Role of Phosphatidylinositol in Cell

118
Role of Phosphatidylinositol in Protein
Anchoring
Ubaidullah Arshad
Acetylcholinesterase, Alkaline Phosphatase
and 5’Nucleotidase are examples of GPI-
Linked proteins
Muhammad

119
Muhammad
Ubaidullah Arshad
Synthesis of Cardiolipin

120
Muhammad
Ubaidullah Arshad
Synthesis of Plaminogen

121
Muhammad
Ubaidullah Arshad
Synthesis of Platelet-Activating Factor

122
Muhammad
Ubaidullah Arshad
Synthesis of Sphingomyelin

123
Muhammad
Ubaidullah Arshad
Degradation of Phospholipids

124
Muhammad
Ubaidullah Arshad
Synthesis of Glycosphingolipids

125
Sphingolipidoses
Lysosomal lipid storage diseases caused by the partial or
total deficiencies of Lysosomal acid hydrolases are called as
Ubaidullah Arshad
Sphingolipidosis
Shell-like inclusion bodies are seen in cytosol
Muhammad
Heart Failure

126
Muhammad
Ubaidullah Arshad

127
Muhammad
Ubaidullah Arshad

128
Sphingolipidoses
Gaucher disease
• Deficiency of β-Glucosidase
• Accumulation of Glucocerebrosides
Ubaidullah Arshad
• Most common lysosomal storage disease
Signs & Symptoms

• Hepatosplenomegaly
• Osteoporosis of long bones
Muhammad
Investigations
• Measuring enzyme activity in cultured fibroblast or peripheral

leukocytes
• Macrophages become engorged with glucocerebroside
• Wrinkled tissue appearance of cytosol of Gaucher's cells in
bone marrow
Treatment
• Bone marrow transplantation
• Substrate reduction therapy
• Enzyme Replacement therapy 129
Muhammad
Ubaidullah Arshad

130
Muhammad
Ubaidullah Arshad

131
Self-Assessment
• Illustrate signaling by Gq protein
• Low-Dose Aspirin therapy is used to lower the risk of stroke and heart attacks. Explain
Ubaidullah Arshad
• Illustrate the Mechanism of action of COX-1 and COX-2 inhibitors

• Give functions of LTB4, PGE2 and PGD2
• Aspirin in contraindicated in Asthma. Comment • Give Diagnosis
Muhammad
• Give synthesis of Lipoxins

• Give isoforms of PGH synthase
• Give Diagnosis
132
133
CONTENTS
• Fatty Liver Disease

• Types of Fatty Liver disease
• Biochemical Defects Leading to fatty Liver
Fatty Liver
disease
Fatty Liver Disease
• Fatty liver occurs when too much fat builds up in liver
cells. Although it is normal to have a tiny amount of fat in
Ubaidullah Arshad
these cells, the liver is considered fatty if more than 5%

of it is fat
• In normal liver Kupffer cells contain lipid in the form of
droplets
• In fatty liver droplets of TAG are found in entire
Muhammad
cytoplasm of hepatocytes

• Types of Fatty Liver Disease
1. Alcoholic Fatty Liver Disease (AFLD)
2. Non-Alcoholic Fatty Liver Disease
(NAFLD)
135
Muhammad
Ubaidullah Arshad

136
Muhammad
Ubaidullah Arshad

137
Muhammad
Ubaidullah Arshad

138
Muhammad
Ubaidullah Arshad

139
Biochemical Defects Leading to Fatty Liver
Disease
The main causes of Fatty Liver Disease Includes
• Ethanol Consumption
Ubaidullah Arshad
• Metabolism of Ethanol results in Increased NADH/NAD+ Ratio

• This inhibits their oxidation and causes increased esterification of fatty acids to form
triacylglycerol, resulting in the fatty liver
• Increased Synthesis of TAG
Muhammad
• Mobilization of free fatty acids from the adipose tissue

• Leads to overproduction of TAG in the liver
• Seen in Diabetes Mellitus , Starvation, Alcoholism and High Fat Diet
• Impairment in Lipoprotein synthesis

• The synthesis of VLDL takes place in the liver requiring Phospholipid and apoprotein B
• A defect in phospholipid synthesis
• A block in apoprotein formation
• A failure of formation/ secretion of lipoprotein 140
Biochemical Defects Leading to Fatty Liver
Disease
• Deficiency of essential fatty acids leads to
Ubaidullah Arshad
decreased formation of phospholipid
• Puromycin, Ethionine, CCl4 ,Chloroform ,

Lead, Phosphorus inhibits protein
synthesis
Muhammad
• Pyridoxine and pantothenic acid leading to

deficiency of ATP impairs lipoprotein
formation
• Orotic acid also causes fatty liver; it is

believed to interfere with glycosylation of
the lipoprotein, thus inhibiting release, and
may also impair the recruitment of
triacylglycerol to the particles.
141
Investigations in Fatty Liver Disease
• The following Investigations are performed

Ubaidullah Arshad
1. LFTs Increased ALT, AST but ALT> AST
in Alcoholic hepatitis AST>ALT
Muhammad
2. USG abdomen

3. Liver Biopsy is Diagnostic
4. CT abdomen
142
Self-Assessment
Ubaidullah Arshad
• What are lipotropic factors. Enlist some lipotropic factors and explain their Action
• Choline deficiency leads to fatty liver disease. Explain
• How will you differentiate between the Viral Hepatitis and Alcoholic Hepatitis based on
LFTs
Muhammad
• What are different endocrine factors that leads to fatty liver disease.

• Vitamin E deficiency leads to fatty liver disease. Explain
143
Muhammad
Ubaidullah Arshad

144

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m.ubaidullah1030@kemu.edu.

Muhammad Ubaidullah Arshad

1 Synthesis & Regulation of Fatty Acids 7-24

3 Synthesis, Storage, Mobilization & Regulation of TAG 44-51

5 Synthesis & Regulation of Cholesterol 59-71

Muhammad Ubaidullah Arshad

7 Metabolism of Lipoproteins 83-109

8 Synthesis of Phospholipids, Glycosphingolipids and Eicosanoids 110-132

• Denovo Synthesis of Fatty Acids

Muhammad Ubaidullah Arshad

Synthesis occurs in following steps

2. Conversion of Acetyl CoA to Malonyl CoA

Muhammad Ubaidullah Arshad

• One ATP per Acetyl CoA is required

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

• Each FAS monomer is a

Muhammad Ubaidullah Arshad

The keto group is reduced to an alcohol by 3-Ketoacyl ACP

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

Palmitate +8 CoA +7 ADP +7 Pi + 6H2O

Muhammad Ubaidullah Arshad

1. Acetyl CoA Carboxylase

Muhammad Ubaidullah Arshad

• Palmitate (16;0) is the product of Fatty

Endoplasmic Reticulum SER

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

• Explain how Metformin lowers serum TAG

Muhammad Ubaidullah Arshad

• β oxidation of Fatty Acids

• Pathway for Energy Generation

Muhammad Ubaidullah Arshad

palmitoyl transferase 1 (CPT-1). Located in outer

Muhammad Ubaidullah Arshad

• Not regulated by CPT-1

Muhammad Ubaidullah Arshad

1. Oxidation producing FADH2

3. Oxidation producing NADH

Muhammad Ubaidullah Arshad

• For even number fatty acids numbers of cycle =

• One cycle of oxidation of a fatty acid produces: NET ATP PRODUCTION BY

1 FADH2 = 1.5 ATP

1 Acetyl CoA =10 ATP

Muhammad Ubaidullah Arshad

Muhammad Ubaidullah Arshad

• Propionyl CoA is then converted into D-Methylmalonyl

• D-Methylmalonyl CoA is converted to L-Methylmalonyl

Muhammad Ubaidullah Arshad

• Methylmalonic acidemia results from Vitamin B12

• Oxidation of Monounsaturated fatty acids require

• Oxidation of Polyunsaturated fatty acids require

Muhammad Ubaidullah Arshad

• Very-long chain fatty acids having carbons more