7/14/2021

University of
Papua New Guinea WHAT ARE LIPIDS?
• Lipids are a heterogeneous group of
Lipid Metabolism compounds, including fats, oils, steroids,
waxes, and related compounds

• Lipids are:
1) relatively insoluble in water and
2) soluble in non-polar solvents (such as
ether or chloroform)
Nigani Willie (MSc, BSc )
Discipline of Biochemistry And Molecular Biology
Division of Basic Medical Sciences, School of Medicine And Health Sciences
University of Papua New Guinea, Taurama Campus

WHAT ARE LIPIDS? WHAT ARE LIPIDS?

• The structure and • The unique physical properties of lipids, due
composition of lipids (mostly to their composition and structure, allows
carbon–hydrogen, C–H lipids to be:
bonds) enables lipids to be: 1) integral part of
cell membranes
1) a rich source of energy
and,
2) an efficient storage of
excess calories in the 2) therefore play an
body important
structural role in
cells.

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LIPIDS LIPIDS
• Lipids are important dietary constituents due to: • The main lipids in the average human diet are:
– Triacylglycerols (or Triglycerides) (TAGs)
1) their high energy value
– Phospholipids (16%)
2) fat-soluble vitamins
– Cholesterols (14%)
3) the essential fatty acids
contained in the fat of – Cholesterol esters (36%)
natural foods
– Free fatty acids (4%)

Lipid Absorption and Formation of Chylomicrons

Lipid Digestion: Emulsification and Micelle Formation
Lumen Enterocyte
oil phase emulsion droplets Short chain
Fatty Acids
DAGs,
MAGs
Blood
Lingual lipase, gastric lipase DAGs,
FFAs
MAGs Glycerol
mostly TAGs FFAs
DAGs,
DAGs, MAGs
MAGs FFAs
Phosphorylated Phospholipids
FFAs glycerols

Pancreatic
Bile acids
lipase
Long chain
mixed micelles Fatty Acids TAGs
DAGs, DAGs,
Mixed
DAGs, MAGs FFAs phospholipids MAGs, MAGs,
micelle
MAGs
FFAs
Lymph
FFAs
solubilise other lipids DAGs,
cholesteryl Chylomicrons
cholesteryl esters MAGs,
FFAs
cholesterol
Bile acids DAGs, DAGs, esters
other lipids MAGs, MAGs,
FFAs FFAs

cholesterol
micelles
Apolipoproteins
TAGs = Triacylglycerols, DAGs = Diacylglycerols, MAGs = Monoacylglycerols, FFAs = Free Fatty Acids

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LIPIDS FATTY ACIDS

• Plasma lipid content: • Fatty acids are present in all

organisms as components of fats
1) Triacylglycerols (16%)
and membrane lipids
2) Phospholipids (30%)
Standing plasma test
• Fatty acids are hydrocarbon
3) Cholesterol (14%) chains of various lengths (4–24
carbon atoms) and degrees of
4) Cholesterol esters (36%) unsaturation that terminate
5) free fatty acids (4%) with carboxylic acid groups

FATTY ACIDS

• Fatty acids are usually esterified to alcohols

(glycerol, sphingosine, or cholesterol)

• Some fatty acids are found in non-esterified

forms
– Known as “free fatty acids” (FFAs)
– FFAs have strong amphipathic properties
– FFAs are usually found in protein-bound
forms

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Glycerol
Fatty acid

Glycerol Glycerol MAG DAG TAG

Structures of 2 types of Triacylglycerols

FATS
• Monoacylglycerols (MAGs) consist of 1 fatty
acid esterified to 1 glycerol

• Diacylglycerols (DAGs) consist of 2 fatty acids

esterified to 1 glycerol

• Triacylglycerols (TAGs) or Triglycerides consist

of 3 fatty acids esterified to 1 glycerol

• As triacylglycerols are uncharged, they are

also referred to as neutral fats

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LIPOGENESIS

• The de novo biosynthesis of fatty acids is Glucose

termed Lipogenesis
Glycolysis

Pyruvate
• Fatty acids are synthesized in an “extra- Pyruvate
mitochondrial system” in the cytosol dehydrogenase
reaction
Lipogenesis
Acetyl-CoA Palmitic Acid
• In most mammals, glucose is the primary
substrate for lipogenesis
• The immediate substrate for lipogenesis is acetyl-CoA

Glucose Glucose

Glycolysis Glycolysis

Pyruvate Pyruvate
Pyruvate Pyruvate
dehydrogenase dehydrogenase
reaction reaction
Lipogenesis Lipogenesis
Acetyl-CoA Palmitic Acid Acetyl-CoA Palmitic Acid

• Lipogenesis occurs in many tissues including

• The end product of lipogenesis is free palmitate liver, kidney, brain, lung, mammary gland and
adipose tissue

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Pyruvate
dehydrogenase CoA

Glucose

Glycolysis

Pyruvate
Pyruvate
dehydrogenase
reaction LIPOGENESIS
Acetyl-CoA Citrate
ATP
citrate
lyase C2
Lipogenesis
Acetyl-CoA Acetyl-CoA Palmitic Acid
Kreb
Cycle
Palmitic acid
Citrate
C16
MITOCHONDRIA CYTOSOL

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LIPOGENESIS: LIPOGENESIS
• Cofactors required for lipogenesis:

– NADPH
Acetyl-CoA Fatty Acid Synthase (FAS)
carboxylase reaction Complex reaction
– ATP

C2 – Mn2+

– Biotin (required by Acetyl-CoA carboxylase)

Palmitic acid
C16
– HCO3− (as a source of CO2)

Acetyl-CoA carboxylase reaction Acetyl-CoA carboxylase reaction:

• Initiation of lipogenesis
Acetyl-CoA Malonyl-CoA
• Acetyl-CoA carboxylase is a “multi-enzyme”
C2 C3
protein
2
• Catalyses the first steps in the lipogenesis
pathway
Acetyl-CoA biotin COO- Acetyl-CoA biotin
• Substrate: Acetyl-CoA, product: Malonyl-CoA carboxylase carboxylase

ADP + Pi ATP + HCO3-

1

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Fatty Acid Synthase Complex (FASC) Fatty Acid Synthase Complex

• In mammals, FASC is
• In yeast, mammals, and birds, the Fatty Acid a dimer comprising
Synthase system is a multi-enzyme of 2 identical
polypeptide complex monomers
(polypeptides)

• FASC contains the vitamin pantothenic acid

(B5) in the form of 4′-phosphopantetheine

• each monomer
contains 7 enzymes
of fatty acid synthase

Fatty Acid Synthase Complex

• The FASC facilitates 7 enzymatic actions:

1) Ketoacyl synthase
2) Acetyl transacylase
3) Malonyl transacylase
4) Hydratase
5) Enoyl reductase
6) Ketoacyl reductase
7) thioesterase (deacylase)

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Fatty Acid Synthase Complex

• The first formation of a carbon–carbon bond

occurs between malonyl and acetyl units
bound to fatty acid synthase. lipogenesis
Acetyl-CoA Palmitate
• After reduction, dehydration, and further
reduction, the acyl enzyme is condensed with C16
C2
more malonyl-CoA and the cycle is repeated
until the acyl chain grows to C16.
• When the growing fatty acid reaches a chain
length of 16 carbons, the acyl group is
hydrolyzed to give the free fatty acid.

LIPOGENESIS SUMMARY

thioesterase
Palmitic Acid 6 H2O
Palmitoyl-CoA
+
Acetyl-CoA 7 CO2
+ +
7 Malonyl-CoA Palmitate
+ +
14 NADPH+ H+ 14 NADP+
+
+
65 ATP 8 CoA

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Esterification to Glycerols Elongation of Fatty Acids

Palmitate Acylglycerols

• 2 locations where elongation can occur are:

Elongation Longer chain
Palmitate
Fatty Acids 1. The Endoplasmic Reticulum
 (Microsomal Fatty Acid Elongase System)
De-Saturation Unsaturated
Palmitate
Fatty Acids
2. The Mitochondria

Esterification to Cholesterol
Palmitate Cholesterol Esters

Microsomal Elongation System Fatty Acid Activation

• The Microsomal Elongation system of Fatty

Acids elongates saturated and unsaturated CoA AMP
fatty acyl-CoAs (from C10 upward) by two ATP PPi
carbons,
Free
• This system uses malonyl-CoA as acetyl donor Acyl-CoA
Fatty Acid Acyl-coA synthase
and NADPH as reductant,

• The pathway is catalyzed by the microsomal

fatty acid elongase system of enzymes

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Elongation of Fatty Acids

• Acetyl donor: malonyl-CoA

CoA AMP
• Reducing agent: NADPH
ATP PPi
Malonyl-CoA
Palmitic Acid Palmitoyl-CoA NADPH+H+
Acyl-coA synthase CO2

Acyl-CoAs Acyl-CoAs
Microsomal Elongation system
Cn Cn+2
n = 10

UNSATURATED FATTY ACIDS

• Unsaturated fatty acids in phospholipids of

the cell membrane are important in
maintaining membrane fluidity

• A high ratio of polyunsaturated fatty acids to

saturated fatty acids (P:S ratio) in the diet is
lowers plasma cholesterol concentrations
(preventing coronary heart disease).

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ESSENTIAL FATTY ACIDS

• Some polyunsaturated fatty acids cannot be

synthesized by the human body and therefore (18:2;9,12)
need to obtained in the diet i.e. essential fatty
acids

• These essential fatty acids are: (18:3;9,12,15)

oLinoleic acid (18:2;9,12)

oα-Linolenic acid (ALA) (18:3;9,12,15)
oArachidonic acid (20:4;5,8,11,14) (20:4;5,11,14)

POLYUNSATURATED FATTY ACIDS • In most animals, double bonds can be

• Unsaturated fatty acids in phospholipids of introduced at the Δ4, Δ5, Δ6, and Δ9 positions,
the cell membrane are important in but never beyond the Δ9 position
maintaining membrane fluidity

• Essential fatty acids are used to form

eicosanoic (C20) fatty acids

• These include: prostaglandins and

thromboxanes and to leukotrienes and
lipoxins

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• In contrast, plants are able to synthesize the DESATURATION OF FATTY ACIDS

nutritionally essential fatty acids by
introducing double bonds at the Δ12 and Δ15
positions.
Microsomal Palmitoleoyl-CoA
Palmitoyl-CoA Δ9 Desaturase

Microsomal Oleoyl-CoA
Stearoyl-CoA Δ9 Desaturase

DESATURATION OF FATTY ACIDS FATTY ACID OXIDATION

• Fatty acids are synthesized from acetyl-CoA
O2 H2O
NADH+ H+ NAD++ • Fatty acids are also oxidized to acetyl-CoA

Stearoyl-CoA
cyt b5
Oleoyl-CoA • However, fatty acid oxidation is not the simple
microsomal Δ9 Desaturase reverse of fatty acid biosynthesis

• Both are entirely different process:

1) Fatty Acid oxidation occurs in mitochondria
2) Fatty Acid biosynthesis occurs in the cytosol

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CYTOSOL

FATTY ACID OXIDATION

Biosynthesis • In the presence of ATP and coenzyme A, the
enzyme acyl-CoA synthetase (thiokinase)
converts a free fatty acid to an “active fatty
acid” or acyl-CoA
Acetyl-CoA Fatty acids
• Acyl-CoA synthetases are found in the
endoplasmic reticulum, peroxisomes, and
inside and on the outer membrane of
β-Oxidation mitochondria

MITOCHONDRIA

The Mitochondria

• The mitochondria has:

– an outer membrane
that is permeable to cytosol
most metabolites
– an inner membrane
that is selectively
permeable and
– a matrix within the
Intermembrane space
inner membrane

Intermembrane space

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FATTY ACID OXIDATION FATTY ACID OXIDATION

• However, carnitine palmitoyltransferase-I,
• Long-chains of acyl-CoA (or FFA) will not
converts long-chain acyl-CoA to acylcarnitine,
penetrate the inner membrane of mitochondria
which is able to penetrate the inner membrane

cytosol cytosol

Intermembrane space Intermembrane space

FATTY ACID OXIDATION FATTY ACID OXIDATION

• Carnitine-acylcarnitine translocase acts as an • Acylcarnitine is transported in, coupled with the
inner membrane exchange transporter transport out of one molecule of carnitine.

Intermembrane space Intermembrane space

matrix matrix

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• The acylcarnitine then reacts with CoA, FATTY ACID OXIDATION

catalyzed by carnitine palmitoyltransferase-II, • Acyl-CoA is reformed in the mitochondrial
located on the inside of the inner membrane. matrix, and carnitine is liberated.

Intermembrane space Intermembrane space

matrix matrix

• In β-oxidation), 2 carbons at a time are cleaved

FATTY ACID OXIDATION from acyl-CoA molecules, starting at the carboxyl
• (carnitine is transported out of the matrix into end.
the intermembrane space)

Intermembrane space

matrix

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• The chain is broken between the α(2)- and β(3)- • The 2-carbon units formed are acetyl-CoA;
carbon atoms—hence the name β-oxidation i.e. palmitoyl-CoA forms 8 acetyl-CoA molecules

Acetyl-CoA
+

Acetyl-CoA
+

Acetyl-CoA
+

Acetyl-CoA
Palmitoyl-CoA +

Acetyl-CoA
+

Acetyl-CoA
+

Acetyl-CoA
+

Acetyl-CoA

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Oxidation of Fatty Acids and ATP Production

• Transport in the respiratory chain of electrons

from FADH2 and NADH will lead to the
synthesis of five high-energy phosphates
(5 ATPs)

• for each of the first seven acetyl-CoA

molecules formed by β-oxidation of palmitate
7 × 5 = 35 ATP molecules

Oxidation of Fatty Acids and ATP Production Oxidation of Unsaturated Fatty Acids

• A total of 8 mol of acetyl-CoA is formed, and • Unsaturated Fatty Acids are oxidised by
each will give rise to 12 mol of ATP on enzymes that normally do -oxidation of
oxidation in the citric acid cycle, saturated fatty acids until a Δ3-cis-acyl-CoA
8 × 12 = 96 mol compound or a Δ4-cis-acyl-CoA compound is
35 + 96 = 131 mol formed (depending on the position of the
double bond)
• Two must be subtracted for the initial activation of
the fatty acid, 131 - 2 = 129 mol • All cis compounds are converted to their
corresponding trans compounds which are
• Thus 129 mol of ATP per mol of palmitate then oxidised

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BIOSYNTHESIS OF ACYLGLYCEROLS
• Acylglycerols constitute the majority of lipids
in the body. Triacylglycerols (TAGs) are the
major lipids in fat deposits and in food

• TAGS have significant roles in lipid transport

and storage and in various diseases such as
obesity, diabetes, and hyperlipoproteinemia

• Both glycerol and fatty acids must be activated

by ATP before they can be incorporated into
acylglycerols

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Glycerol kinase
Glycerol sn-Glycerol 3-Phosphate 1,2-Diacylgycerol 3-Phosphate

Acyl-CoA glycerol-3-phosphate Phosphatidate

acyltransferase phosphohydrolase
Pi

1-Acylgycerol 3-Phosphate 1,2-Diacylgycerol

Acyl-CoA 1-glycerol-3-phosphate Acyl-CoA Diacylglycerol

acyltransferase acyltransferase

1,2-Diacylgycerol 3-Phosphate Triacylglycerol

*1,2-diacylglycerol phosphate = phosphatidate

BIOSYNTHESIS OF PHOSPHOLIPIDS
Diacylglycerol
acyltransferase
• Phospholipids are the main constituents of
biological membranes
sn-Glycerol 3-Phosphate 1,2-Diacylgycerol Triacylglycerol

• Phospholipids are lipids that contain a

phosphate residue that is esterified with the
hydroxyl group at C-3 of glycerol

• Due to this residue, phospholipids have at

least one negative charge at a neutral pH.
Lysophosphatidate Phosphatidate
(1-Acylgycerol 3-Phosphate) (1,2-Diacylgycerol 3-Phosphate)

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BIOSYNTHESIS OF PHOSPHOLIPIDS BIOSYNTHESIS OF PHOSPHOLIPIDS

• Major phospholipids include:
• Phosphatidyl-choline (lecithin), the most
1) Phosphatidylcholine (lecithin) abundant phospholipid is synthesised from
1,2-diacylglycerol
2) Phosphatidylethanolamine (cephalin) CDP-choline

3) Phosphatidylserine
CDP-choline: Diacylglycerol
4) Phosphatidylinositol Phosphocholine Transferase

1,2-Diacylgycerol Lecithin
5) Sphingomyelin (Phosphatidyl-choline)

Choline
ATP

Choline kinase

ADP

Phosphocholine CDP-choline

CDP
CTP: Phosphocholine Cytidyl Transferase
CDP-choline: Diacylglycerol
Phosphocholine Transferase
PPi Diacylglycerol
1,2-Diacylgycerol Lecithin
CDP-choline Lecithin (Phosphatidyl-choline)
CDP-choline: Diacylglycerol
Phosphocholine Transferase

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BIOSYNTHESIS OF PHOSPHOLIPIDS

• Phosphatidylethanolamine (cephalin) is a
phospholipid formed in a simlar way to that of
lecithin.
CDP-ethanolamine
• Cephalin structure contains an ethanolamine
residue instead of choline
CDP-choline: Diacylglycerol
Phosphoethanolamine Ethanolamine
Transferase
Diacylglycerol
1,2-Diacylgycerol Cephalin
CDP-ethanolamine CDP-choline: Diacylglycerol
Cephalin (Phosphatidylethanolamine)
Phosphocholine Transferase

Ethanolamine
ATP
Ethanolamine
kinase

ADP

Phosphoethanolamine CDP-ethanolamine

CDP
CTP: Phosphoethanolamine Cytidyl Transferase
CDP-choline: Diacylglycerol
Phosphoethanolamine Ethanolamine
Transferase
PPi Diacylglycerol
1,2-Diacylgycerol Cephalin
CDP-ethanolamine CDP-choline: Diacylglycerol
Cephalin (Phosphatidylethanolamine)
Phosphocholine Transferase

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BIOSYNTHESIS OF PHOSPHOLIPIDS Ketogenesis

• Phosphatidylserine is formed from cephalin • When fatty acid oxidation occurs at high rates,
directly by reaction with serine the liver produces large quantities of
acetoacetate and β-hydroxybutyrate.
Serine
• Acetoacetate continually undergoes
Cephalin Phosphatidylserine spontaneous decarboxylation to yield acetone

• Acetoacetate, β-hydroxybutyrate and Acetone

are collectively known as the ketone bodies

Acetyl-CoA + Acetyl-CoA
thiolase

Acetoacetyl-CoA + Acetyl-CoA

HMG-CoA synthase

HMG-CoA

HMG-CoA lyase
Acetyl-CoA

Acetoacetate
*HMG-CoA = 3-hydroxy-3-methylglutaryl-CoA

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Ketosis
• Higher than normal quantities of ketone
bodies present in the blood is called
ketonemia (or hyperketonemia); in urine is
called ketonuria. The overall condition is
called ketosis.

• Continuous production and excretion in large

quantity progressively depletes the alkali
reserve, causing ketoacidosis

BIOSYNTHESIS OF CHOLESTEROL

Acetyl-CoA + Acetyl-CoA
Mevalonate
thiolase
3 ATP
Mevalonate Kinase
Acetoacetyl-CoA + Acetyl-CoA Phosphomevalonate
Kinase
HMG-CoA synthase Diphosphomevalonate
Kinase Mg
+

HMG-CoA Diphosphomevalonate
Decarboxylase 3 ADP
NADPH+H+
HMG-CoA reductase Isopentenyl diphosphate
NADP+

Mevalonate

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Isopentenyl diphosphate
Squalene
Isopentenyldiphosphate
Isomerase
Squalene Epoxidase
Isopentenyl
Dimethylallyl diphosphate +
diphosphate Oxidosqualene:
Lanosterol Cyclase
Cis-prenyl
Transferase
Lanosterol
Isopentenyl
Geranyl diphosphate +
diphosphate
Cis-prenyl
Transferase

Farnesyl diphosphate
Squalene Synthetase

Cholesterol
Squalene

Lecithin Cholesterol Acyltransferase (LCAT)

• Free cholesterol and lecithin on the surface of

the lipoprotein, HDL, are converted into Cholesterol + Lecithin
cholesteryl esters and lysolecithin by LCAT
LCAT
• Cholesterol esters move into the hydrophobic
core of the HDL during transportation while
the lysolecithin is transferred to albumin in Cholesterol ester + Lysolecithin
plasma

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STUDY QUESTIONS
Lecithin Cholesterol Acyltransferase LCAT • Why are lipids important in the human diet?
• What are lipids? What are their biological roles?
• What is the structural difference between a fatty acid and an acylglcyerol?
• This generates a non polar core, forming a • What is lipogenesis? What is the immediate substrate for lipogenesis?
What is the end product of lipogenesis?
spherical, pseudomicellar HDL covered by a • Name the substrate and product of the Acetyl-CoA carboxylase reaction.
surface film of polar lipids and apolipoproteins • What are the substrates and end products in the Fatty Acid Synthase
Complex reactions?
• Explain what Fatty Acid Elongation means.
• In this way, the LCAT system is involved in the • What is meant by Fatty Acid Activation?
• What does de-saturation of fatty acids mean?
removal of excess unesterified cholesterol • What is meant by the term “essential fatty acids”?
from lipoproteins and tissues • Briefly explain how β-oxidation of fatty acids occur?
• Briefly explain how the biosynthesis of acylglycerols occur.
• Briefly explain how the biosynthesis of phospholipids occur
• What are Ketone bodies? How are they produced? What is their
significance?
• What is the biological role of cholesterol?

References

• Murray RK, Granner DK, Mayes, Rodwell VW. Harper’s

Biochemistry 24th Edition 1996
• Koolman J and Roehm KH. Colour Atlas of Biochemistry 2nd
Edition 2005
• Cox RA and Garcia-Palmieri MR. The Cardiovascul System:
Cholesterol, Triglycerides, and Associated Lipoproteins in
Laboratory, 31: 153-160
• Gaw A, Cowan RA, O’Reily DSt.J, Stewart MJ and Shepherd.
Clinical Biochemistry (An Illustrated Text), 1995, Churchill
Livingstone
• Burtis CA and Ashwood ER (editors), Tietz Fundamentals of
Clinical Chemistry 4th edition, 1996, Saunders

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