Lipid metabolism

Dr Amany Mohamed
Department of Medical Biochemistry & Molecular Biology
Faculty of Medicine, Helwan University
 Lecture’s objectives
• Point out importance of pancreatic lipase & bile salts in lipid
decomposition, disorders associated with defects in this process
• Recognize how lipogenesis takes place in all tissues, its importance
& how the process is regulated
• Outline fatty acid oxidation pathway & how this leads to production
of large quantities of energy.
• Point out the importance of cholesterol to the cell, its various
functions, how it is synthesized in the body, its balance in tissues,
its normal level in blood
• Recognize that ketone bodies are important fuel for extrahepatic
tissues in prolonged fasting. Understand that overproduction of
ketone bodies leads to ketosis& ketoacidosis
• Identify the main groups of plasma lipoproteins, how they are
formed, the role of each type in lipid transport
Digestion and Absorption
 Emulsification & Digestion
Lipids are hydrophobic (water insoluble).
Pancreatic lipase is soluble in water and can
interact only at the surface of lipids.
Bile salts help pancreatic lipase by
emulsifying lipids (breaking fat to small
molecules).
GIT hormones like secretin &
cholecystokinin (+) pancreatic lipase
secretion.
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 Lipid Absorption
Small lipid fragments:
Glycerol & Short Chain FAs (SCFAs)are
absorbed directly into the blood stream.

Long chain FAs, cholesterol & B-

monoacylglycerol are absorbed with bile
salts as micelles.
 Resynthesis of TAG &
Cholesterol Ester
Within the intestinal cells, B-monoacyl
glycerol resynthesize TAG.
Cholesterol recombine with fatty acid to
give Cholestryl ester.
such hydrophobic molecules combine
with phospholipids & water soluble
proteins, forming chylomicrons that
appear in circulation.
 Read
Lipid Absorption Only
 Lipid Metabolism
Lipolysis & Fatty Acid oxidation
 Lipolysis
by hormone sensitive lipase (HSL).
 Lipolysis
Glycerol is used for synthesis of glucose
via gluconeogenesis
Fatty acids are transported in circulation
bound to albumin to reach peripheral
tissues to be oxidized via beta oxidation
to release more energy
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Glycerol to glucose Only
 O

  C
4
3 1 O−
2

fatty acid with a cis-9

double bond

Free fatty acids are transported in the blood

bound to albumin, a plasma protein produced by
the liver.
Several proteins have been identified that facilitate
transport of long chain fatty acids into cells
 ADIPOSE TISSUE
TG Fatty acids

Fatty acids - bound to albumin

CIRCULATION
(10 fatty acids/albumin monomer)
(free fatty acids, FFA)

MUSCLE, HEART MUSCLE, RENAL CORTEX

Fatty acid activation, transport into the mitochondria, β-oxidation
 Fatty Acid oxidation

Major Pathway: β-oxidation

This pathway takes place inside the
mitochondrial matrix of most aerobic
tissues.
Fatty acids require a “carnitine
transport system” for transporting
fatty acids across the mitochondrial
membrane, since this membrane is
impermeable to fatty acids.
 Energy yield from fatty acid oxidation is
much higher than glucose oxidation
Example:
Oxidation of one molecule of palmitic acid
(16C) produces 106 ATP, yet glucose is
considered the preferable source for
energy production.
 Example: Energy of palmitoyl
~Co A (16 C) oxidation
Number of cycles= n/2 -1 = 7 cycles Read Only
Number of acetyl ~Co A = n/2 =8
→ So, 7 NADH, each provide 2.5 ATP when oxidized in the
ETC 7X2.5=17.5 ATP
→ 7 FADH2 each provide 1.5 ATP when oxidized in the ETC
7x 1.5=10.5 ATP
→ 8 acetyl ~Co A , each provides 10 ATP when converted to
CO2& H2O by the TCA cycle 8x10= 80 ATP
So total energy yield of oxidation of palmitoyl ~Co A = 17.5
+ 10.5 + 80 = 108 ATP
As 2 molecules of ATP are used in the activation of a
molecule of fatty acid →Therefore, there is a net yield of
106 molecules of ATP
Fatty Acid Synthesis
)LIPOGENESIS(
 Introduction
✓ There are three systems for the synthesis of
fatty acids

1. De novo synthesis of FAs in cytoplasm

2. Chain elongation in microsomes

3. Fatty Acid Desaturation.

 Sources of acetyl CoA
Acetyl-COA is the building unit of fatty acids. It is derived
from:

1. Carbohydrate: Via the oxidative decarboxylation of

pyruvate in the mitochondria.

2. Fat: Oxidation of fatty acids is the richest source of acetyl

CoA e.g. palmitate gives 8 acetyl CoA while glucose gives
two.

3. Protein: Ketogenic amino acid is converted to acetyl CoA or

acetoacetate. Glucogenic amino acid can be converted to
pyruvate, which gives acetyl CoA.
 Fate of acetyl CoA:
Oxidation through citric acid cycle.

Lipogenesis: formation of fatty acids.

Ketogenesis: formation of ketone bodies.

Steroids formation: cholesterol, bile salts, and

steroid hormones.

Formation of acetyl choline.

Cholesterol Metabolism
Read Only
 Cholesterol synthesis
• Synthesized in all tissues
• Major sites for synthesis: liver, adrenal
cortex, testes, ovaries and intestine.
• All carbon atoms are derived from acetyl
CoA.
• Enzymes involved in biosynthesis are partly
located in ER and partly in cytoplasm.
 Cholesterol synthesis
1. Synthesis of HMG CoA
• HMG CoA is present in
both cytosol and
mitochondria of liver
• Mitochondrial-
ketogenesis
• Cytosolic – cholesterol
synthesis
 Cholesterol synthesis
2. Synthesis of mevalonic acid
• This is the key step,
• occurs in cytosol.
• HMG CoA reductase is
the rate limiting enzyme
in cholesterol synthesis
(it is stimulated by
insulin & thyroxin and
inhibited by glucagon &
cortisone).
HMG CoA Reductase Regulation
Gene
Cholesterol

Transcription

Translation

Insulin
HMG CoA Reductase
Glucagon Thyroxin
Cortisones
Statins
HMG Cholesterol
CoA
 Excretion of cholesterol

• By conversion into bile acids and bile salts-

excreted in the feces
– Secretion of cholesterol in bile
– Transported to intestine for elimination
• In the intestine, some cholesterol is
converted by bacteria into coprostanol and
before excretion
 Hypercholesterolemia

• High conc. of cholesterol in blood

• Leads to atherosclerosis
• Statin drugs are used to decrease plasma
cholesterol levels
• Statins are structural analogs (similar) of
HMG CoA reductase
• Statins inhibit enzyme activity by
competitive inhibition
 Primary hypercholestrolemia
Familial hypercholestrolemia
-Genetic (inherited) defect in LDL
receptor, necessary for cholesterol upatke
by the cell.
-LDLc (bad cholesterol) will be elevated in
blood.
-Such patients present with premature
(early in life) hypercholesterolemia.
(Polyunsaturated fatty acids).
KETONE BODIES
METABOLISM
INTRODUCTION

When there is a adequate balance between .

Lipid and carbohydrate metabolism, most of
the acetyl CoA produced from the B-oxidation
pathway is further processed through the
citric acid cycle.

The first step of the citric acid cycle involves

the reaction between oxaloacetate and
acetyl CoA. Sufficient oxaloacetate
must be present for the acetyl CoA to
react with.
Certain body conditions upset the lipid-
carbohydrate balance required for acetyl CoA
generated by fatty acids to be processed by
the citric acid cycle. These condition include:
➢ dietary intake high in fat and low in
carbohydrates
➢ Diabetic condition where the body cannot
adequately processed glucose even though it is
present
➢ Prolonged fasting condition, including starvation,
where glycogen supplies are exhausted.

Under these conditions, the problem of adequate

oxaloacetate supplies arises, which is complicated by the
body’s using oxaloacetate that is present to produce glucose
through gluconeogenesis.
Ketone body types: acetoacetate, B-
hydroxybutyrate and acetone.

They are produced from acetyl CoA

when an excess of acetyl CoA from fatty
acid degradation accumulates because
of triacylglycerol- carbohydrate
metabolic imbalances.
 Ketogenesis
synthesis of ketone bodies
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Only
 adipose Fatty liver
tissue
Fatty Read
Acids
Triglyceride Acids Only
albumin 2
Glucagon
1 Fatty Acids

3
Epinephrine Hormo -
Glucocortic ne oxidation
oids + Sensiti Albumi
ve
Acetyl Co
Glyce n
Lipase TCA
A
rol Cycl
Fatty e
Fatty
Acids Acids Ketone
Bodies

Energy for the Brain and

Ketone bodies are
synthesized only in liver
to be used by other
tissues as fuel source in
prolonged fasting or
starvation.
 Ketolysis
oxidation of ketone bodies
“alternative body fuel”
 β-Hydroxybutyrate
dehydrogenase
β-Hydroxybutyrate
Succinyl CoA
NAD+ NAD
H CoA
The liver does not have enzymes to transferase
oxidize ketone bodies thus:

“Ketone bodies are synthesized in

the liver but utilized in the
peripheral tissues”. CoA-SH
Thiolas
e

KETOLYSIS
KETOSIS/ KETONEMIA & KETONURIA

Ketosis is a disorder of excessive production of ketone bodies

The concentration of total ketone bodies in blood of well fed mammals does

not exceed 3mg/dl.

In diabetic individuals with severe ketosis, urinary excretion of ketone bodies

increases and blood concentration may reach 90 mg/dl. There is fruity odor of

breath caused by increased production of acetone.

Blood level of ketone bodies increased – Ketonemia

Excretion of ketone bodies in urine increased - Ketonuria

 CLINICAL SIGNIFICANCE of KETOACIDOSIS

Ketone bodies (acetoacetic acid & 3-OH Butyric acid ) are

acidic in nature

When ketone bodies are released in large quantities the

body tries to normalize the pH by buffering mechanisms but
they may result in KETOACIDOSIS.

In severe ketoacidosis, cells begin to lose ability to use

ketone bodies also. They can inhibit brain centers leading
to coma.
CLINICAL FEATURES OF KETOSIS

Acidosis
Smell of acetone in patient's breath.
Osmotic diuresis induced by ketonuria
may lead to dehydration.
Sodium loss (The ketone bodies are
excreted in urine as their sodium salt)
Dehydration
Coma
Causes of KETOACIDOSIS

The main cause is:

Excess fatty acid oxidation by the liver due
to enhanced lipolysis.

Enhanced lipolysis (Excess mobilization of fat from

adipose tissue) occurs when Insulin : Glucagon ratio
decreases).
This ratio decreases in case of:
1.What wUncontrolled Diabetes Mellitus
1.Diabetic ketoacidosisProlonged Stati
2. Starvation Ketoacidosis
Lipid Transport
and Storage
 LIPIDS ARE TRANSPORTED IN
THE PLASMA AS LIPOPROTEINS

Lipoproteins Consist of a Nonpolar Core & a

Single Surface Layer of Amphipathic Lipids

The Distribution of Apolipoproteins

Characterizes the Lipoprotein

Lipid transport & storage 71

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 Lipoproteins

Core of TG and CE
Surface of phospholipids and some
cholesterol
Apolipoproteins (regulators of LP
metabolism)
Chylomicrons, VLDL, IDL, LDL, HDL
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 Types of lipoproteins
Chylomicrons: carries absorbed lipid from intestine to
peripheral tissues via circulation and its ruminants taken up
by the liver
VLDL: carries lipid synthesized by the liver to peripheral
tissues via circulation and its ruminants makes LDL in
circulation
LDL: synthesized in circulation from VLDL carries
cholesterol to peripheral tissues and to the liver
HDL: synthesized in liver and intestine act as means
whereby cholesterol can be transported from peripheral
tissues to the liver for excretion.
The transport of cholesterol from tissues to the liver is
known as reverse cholesterol transport
 CLINICAL ASPECTS

Imbalance in the Rate of TG Formation in

the liver & Export Causes Fatty Liver

Ethanol Also Causes Fatty Liver

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 CLINICAL ASPECTS
Clinical Significance of HDL
The level of HDL in serum is inversely related to the incidence
of myocardial infarction. As it is "anti-atherogenic" or
"protective" in nature, HDL is known as "good cholesterol" in
common language.

It is convenient to remember that"H" in HDL stands for

"Healthy". HDL level below 35 mg/dl increases the risk, while
level above 60 mg/dl protects the person from coronary artery
diseases. 77
 CLINICAL ASPECTS
LDLc / HDLc Ratio:
❑ LDL / HDL cholesterol ratio is agood predictive marker of coronary heart

disease.

❑ The desirable ratio is less than 3.5.

❑ To avoid atherosclerosis raise HDLc and lower LDLc.

❑ HDLc can be raised by regular muscler exercise, caloric restriction, stop

smoking .

❑ LDLc can be lowered by taking whole grain bread, fruits, vegetables,

beans& peas and by avoiding high saturated fat (present in fatty meat,
palm oil & full fat dairy).
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