LIPIDS

Olga Tagadiuc
Tagadiuc,
MD, PhD, associated professor
Head of the Biochemistry Department

Obj ti
Objectives :
1. Functions and classification
2. Digestion and absorption
3. Plasma lipoproteins metabolism
4. Liposoluble vitamins
5
5. Catabolism of lipids:
oxidation of triglycerides
oxidation of fatty acids
6. Biosynthesis of lipids:
biosynthesis of fatty acids
biosynthesis of triglycerides
biosynthesis of phosphoglycerides
77. Cholesterol metabolism
8. Ketone bodies metabolism
9
9. Regulation of lipid metabolism
Functions of lipids
1. Energetic
2
2. S
Stucturall
3. Regulatory
g y
4. Co-enzymatic
5
5. Provide body with essential fatty acids and fat
soluble vitamines (A, D, E, K )
6 Fixation
6. Fi ti off internal
i t l organs
7. Provide insulation against temperature changes
8. Etc.

Clasification of lipids according to their

chemical structure
I class: Monocomponent or unsaponifiable lipids
1. fatty acids
2 higher alcohols,
2. alcohols aldehydes
aldehydes, ketones
3. isoprenoids and their derivatives carotenoids, vit. A,
vit K.
vit. K
II class: Polycomponent or saponifiable lipids
1 Si
1. Simple triglycerides,
i i waxes
2. Complex phospholipids, sphingomyelins,
glycolipids
i i
III class: Sterols
1. cholesterol and its esthers
2. biliaryy acids
3. steroid hormones
 Clasification of lipids according to
their biological role

I class: structural lipids

II class: reserve lipids

Digestion and
absorption of lipids
 The major
j dietary
i lipids
i i are:

Triglicerides

Phospholipids

Cholesterol and its esters

Digestion of lipids takes place:

In the mouth due to the presence of lingual lipase

In the stomach due to the presence of gastric lipase and

a higher pH than in adults

In the duodenum and small intestine due to the

presence of bile acids and pancreatic enzymes.
Digestion
Di ti iin dduodenum
d and
d small
ll
intestine includes:

Emulsification
Hydrolysis
yd o ys s
Mixed micelle formation

Hydrolysis of triglucerides
Triglyceride molecules are digested by
pancreatic lipase to yield
a monoglyceride and 2 fatty acids
 H d l i off phosphoglycerides
Hydrolysis h h l id
Final products: The enzymes
y are:

1. glycerol, 1. phospholipase A1

2. fatty acids, 2 phospholipase

2. h h li A2
3 phosphate
3. 3. p
phospholipase
p p C
4. a non-lipidic 4. phospholipase D
compound

Hydrolysis of cholesteryl esters

Absorption and transport of lipids includes:
1. transfer of mixed micelles into enterocytes
2. re-synthesis of triglycerides in enterocytes
3. formation of chylomicrons
4. transport of chylomicrons to the tissues

Chylomicrons
role - lipid
uptake from the
intestine and
t
transport t tto
target
g tissues

target tissues
muscle
l and d
adipose
p tissue
 Liposoluble Vitamins

Liposoluble vitamins are:

A: retinol,
retinol retinal and retinoic acid
D:
D2 ergocalciferol
D3 - cholecalciferol
E: tocopherols and tocotrienols
K
K:
K1 (phylloquinone) in green vegetables
K2 (menaquinone) produced by intestinal bacteria
K3 is synthetic menadion
 Vitamins A - Biologic
g Effects

1. Vision
2. Resistance to infectious disease
3. Epithelial cell "integrity"
4
4. Bone remodeling
5. Reproduction
p

Vitamin D
Biosynthesis in the skin
 Vitamin D
1st hydroxylation in the liver

Vitamin D
2nd hydroxylation in the kidneys
 Vitamin D biological role
In the intestinal epithelium - induce
production of the protein responsable for
calcium absorption

Vit i E biological
Vitamin bi l i l role
l

1. Antioxidant
2 Enzymatic
2. E i activity
i i regulator
l
3 Influence gene expression
3.
4. Inhibits platelet aggregation
5. Protects lipids and prevents the
peroxidation
id ti off polyunsaturated
l t t d fatty
f tt acids
id
 Vit i K
Vitamin

K1 - phylloquinone
K2 - menaquinone
K3 - synthetic
menadion

Vit i K biological
Vitamin bi l i l roll

Is the cofactor of the

-glutamylcarboxylase
 Vitamin K biological rol

Human Gla-containing proteins:

Osteocalcin
Matrix-Gla-protein (MGP)
Coagulation factors
Anticoagulation proteins

Triglycerides
Metabolism
 Triglycerides
Catabolism

Catabolism of Stored Triglycerides

Triglycerides - the principal form

off energy storage
t iin organism
i
Triglycerides
Ti l id - stored
t d iin the
th
adipocytes of adipose tissue.
Catabolism of triglycerides stored in adipose tissue

TGLG
trilyceride
lipase

DGL
diglyceride
lipase

MGL -
monoglycer
l
idlipase

http://themedicalbiochemistrypage.org/lipid-synthesis.php
 Biosynthesis of
Triglycerides

Biosynthesis of Triacylglycerols (1)

1. major building block:
dihydroxyacetone phosphate
glycerol
fatty
f tt acids
id
2. Major intermadiate compounds:
glyceraldehyde-3-phosphate
p phosphatidic
p acid
 Biosynthesis of Triacylglycerols (2)
Glycerol-3-phosphate can be formed in two ways

1._______________________________________________

Biosynthesis of Triacylglycerols (2)

Glycerol-3-phosphate can be formed in two ways

II. ______________________________________________
Biosynthesis
y of Triacylglycerols
ygy ((3))

Biosynthesis of Triacylglycerols (3)

Biosynthesis of Triacylglycerols (4)

Insulin promotes the conversion of

carbohydrate into triacylglycerols .

Oxidation of glycerol
Gl
Glycerol
l Oxidation
O id i step I

Gl
Glycerol
l Oxidation
O id i step II
 Glycerol oxidation energetic output
Complete glycerol oxidation in aerobic conditions
gives
i 22 ATP

Fatty acids oxidation

Oxidation of fatty acids
Stages:
1. activation of fatty acid to acyl-CoA (cytosole)
2. transfer of acyl-CoA through the
mitochondrial membrane
3. b-oxidation the pathway of fatty acids
degradation (mitochondrial matrix)

1 Activation of Fatty Acids

1.
Fatty acid + ATP + HSCoA > Acyl-CoA + AMP + PPi
 2. Transfer of
acyl-CoA
th
through
h th
the
mitochondrial
membrane

-Oxidation of Saturated Fatty Acids (1)

 O id ti off Saturated
-Oxidation S t t d Fatty
F tt Acids
A id (2)

O id ti off Saturated
-Oxidation S t t d Fatty
F tt Acids
A id (3)
 O id ti off Saturated
-Oxidation S t t d Fatty
F tt Acids
A id (4)

-Oxidation
Oxidation of
Saturated
Fatty Acids
Fi l products
Final d off the
h oxidation
id i off fatty
f acids
id

acyl-CoA
y

acetyl-CoA

FADH2 and NADH

E
Energetic
ti output
t t off fatty
f tt acids
id oxidation
id ti

The overall nr. of ATP =

 O id ti off Unsaturated
Oxidation U t t dFFatty
tt
Acids
requires an additional enzyme,
enzyme enoyl-CoA
enoyl CoA
isomerase.
This enzyme repositions the double bond,
converting the cis isomer to a trans isomer,
isomer a
normal intermediate in oxidation.

Oxidation of Unsaturated Fatty Acids

O id ti off Odd-Chain
Oxidation Odd Ch i FFatty
tt AAcids
id
Requires Three Extra Reactions
Nr. I

Oxidation ofNr.
Odd-Chain
II and Nr.III
Fatty Acids
Biosynthesis of Lipids

Fatty Acid
Synthesis
 Fatty
y Acids biosynthesis
y occurs in cytoplasm.
y p

The process requires:

acetyl-CoA
t lC A
NADPH
Enzyme complex - Fatty acid synthetase

St
Stages off Fatty
F tt Acid
A id S
Synthesis
th i

1 Transport of Acetyl-CoA from

1.
mitochondria to cytoplasm
2. Synthesis of malonyl-CoA
3. Actual synthesis of fatty acids
 Transport of Acetyl
Acetyl-CoA
CoA
from mitochondria to cytoplasm

S
Synthesis
i off malonyl-CoA
C A (1)
 A t l synthesis
Actual th i off fatty
f tt acids
id (2)
Fatty Acid Synthase prosthetic groups:
Belongs to a Cys residue

Belongs
g to p
phosphopantetheine
p p

A t l synthesis
Actual th i off fatty
f tt acids
id (3)
Enzyme complex fatty acid synthase
1. acetyl-CoA transacylase
2.. malonyl-CoA
o y Co transacylase
s cy se
3. -keto-ACP synthase
4. -keto-ACP reductase
5. 33-hydroxyacyl-ACP
hydroxyacyl ACP dehydratase
6. enoyl-ACP reductase
7. acyl-ACP transferase
8. thioesterase
A t l synthesis
Actual th i off fatty
f tt acids
id (6)
Substrate attachment

A t l synthesis
Actual th i off fatty
f tt acids
id (6)
 A t l synthesis
Actual th i off fatty
f tt acids
id (7)

The cycle of this reactions repete untill

palmitil-ACP
l itil ACP fformation
ti

A t l synthesis
Actual th i off fatty
f tt acids
id (8)
Palmitic Acid Biosynthesis requires:
7 cycles; 1 acetyl; 7 malonils; 14 NADPH.H+

Synthesis of Unsaturated Fatty Acid

 Biosynthesis of
Membrane Lipids

Biosynthesis of
Glycerophospholipids
 Biosynthesis of membrane lipids

Glycerophospholipids are produced in 2 ways:

I. de novo
II.salvage pathway from existing building blocks

De novo biosynthesis of glycerophospholipids

 (1) Salvage pathway
of glycerophospholipids biosynthesis
choline is re-used ("salvaged")
( salvaged ) by being
phosphorylated then converted into
CDP h li by
CDP-choline b condensation
d ti with
ith CTP.
CTP A
diacylglycerol displaces CMP from CDP-choline,
producing phosphatidylcholine

An analogous salvage pathway converts

ethanolamine obtained in the diet into
phosphatidylethanolamine

CHOLESTEROL
METABOLISM
 CHOLESTEROL STRUCTURE

Ch l t l functions
Cholesterol f ti

1. Cholesterol is a structural element of

membranes
 Ch l t l functions
Cholesterol f ti
2. Cholesterol is a precursor of steroid
hormones and bile acids
3. Cholesterol is a precursor of vitamin D

Biosynthesis of cholesterol (1)

aprx. 50% produced de novo

aprx
15% in the liver
10% in the intestine
 Biosynthesis of
cholesterol
( )
(2)

Biosynthesis of cholesterol (3)

HMGR is
subject to
complex
regulatory
controls
 Biosyn-
osy
thesis of
choles-
t l (4)
terol

Bi
Biosynthesis
th i off cholesterol
h l t l (5)
The HMGR is controlled by 4 mechanisms:
1. feed-back inhibition,
2 control of gene expression,
2. expression
y
3. rate of enzyme degradation,
g ,
4. phosphorylation-dephosphorylation.
Properties
P ti andd lipidic
li idi composition
iti off
plasma lipoproteins

Metabolism of
Ketone Bodies
 Ketone bodies
acetoacetate
b-hydroxybutirate
acetone

Role
Energy provider

Biosynthesis
Bi h i
Sustrate: acetyl-CoA
Location: liver

Oxidation of Ketone Bodies as Fuel

 Regulation of Lipid
Metabolism

Regulation of lipid metabolism

M t b li off lipids
Metabolism li id depends
d d on:
a dietary supply of lipids and carbohydrates
a.
b. neuro
neuro-hormonal
hormonal regulation
Regulation of lipid metabolism

1 A large dietary intake of carbohydrate

1. carbohydrate-rich
rich food
induces a significant production of triglycerides
and cholesterol

2. Vegetable oils rich in lipotropic factors prevent

an excessive accumulation of cholesterol and its
deposition in blood vessels

Regulation of lipid metabolism

The dietary lipotropic factors exerts a marked
effect on the biosynthesis of phospholipids and
ti l
triglycerides.
id
The dietaryy lipotropic
p p factors:
a. promotes phospholipids production in the liver
b decrease
b. d ti l
triglycerides
id production
d ti in i the
th liver
li
Lipotropic
p p factors are: choline, betaine,
methionine, inositol etc.
Disorders of lipid metabolism
I. Hyperlipidemias II Lipidoses
II.
(elevated concentration of (excessive lipid deposition
lipids in blood) in tissues)
1. Primary or 1. Primary or
h dit
hereditary hereditary
2. Secondaryy to 2 Secondary to
2.
an undrlying an undrlying
disease disease

Disorders of lipid metabolism

Tissue lipidoses
p
Primary y lipidoses
p arise from defects of the
enzymes involved in lipids metabolism, i.e.
enzymes responsible for degradation of
shingolipids
 Disorders
Di d off li
lipid
id metabolism
t b li
Secondary tissue lipidoses
Atherosclerosis
When the cholesterol synthesized and obtained
in the diet exceeds the amount required for the
synthesis of membranes, bile salts, and steroids
pathological accumulations of cholesterol in
bl d vessels
blood l (atherosclerotic
( h l i plaques)
l ) can
developp in humans,, resultingg in obstruction of
blood vessels (atherosclerosis).

Disorders of lipid
p metabolism
Secondary tissue lipidoses
Atherosclerosis
risk factors:
age,
male sex,
dyslipidemia,
hypertension,
smoking,
diabetes,
obesity
obesity,
sedentary
lif t l
lifestyle
 Disorders
Di d off li
lipid
id metabolism
t b li
Secondary tissue lipidoses - Atherosclerosis