LIPID METABOLISM • Salivary enzymes (water soluble) in the mouth

have no effect on lipids (TAGs), which are water

Fatty Acids
insoluble
• contains a long hydrocarbon chain and a
• In the stomach, most, not all, TAGs change
terminal carboxylate group. The hydrocarbon
physically to small globules or droplets called
chain may be saturated (with no double bond)
chyme, which floats above other material
or may be unsaturated (containing double
bond). o It is a physical, not chemical, process

• Fatty acids can be obtained from:

• Diet Lipid Digestion in the Stomach

• Adipolysis • Starts in the stomach

• De novo synthesis • Gastric lipase enzymes hydrolyze TAG

ester bonds

• About 10% of TAGs are hydrolyzed in

Functions of Fatty Acids
the stomach
Lipids can serve a diverse range of functions within a
• Triacylglycerols -> monoacylglycerol +
cell, including:
free fatty acids
1. Storage of energy for long-term use (e.g.
triglycerides, triacylglycerols)

2. Hormonal roles (e.g. steroids such as estrogen

and testosterone)

3. Insulation – both thermal (triglycerides) and

electrical (sphingolipids)

4. Protection of internal organs (e.g. triglycerides High-fat foods stay in the stomach for longer time, and
and waxes) a high-fat meal causes a feeling of being full for a longer
period of time.
5. Structural components of cells (e.g.
phospholipids and cholesterol)
Lipid Digestion in the intestinal cells

Fatty acids are fuel molecules • Chyme enters into small intestine and is
emulsified (stabilization of colloidal suspension)
Stored as triacylglycerols with bile salts
Mobilized from triacylglycerols and they are being • Pancreatic lipase hydrolyzes ester bond linkages
constitized to meet the energy needs of a cell or between fatty acid units and glycerol
organism
• Fatty acids, monoacyglycerols, and bile salts
combine into small droplets called micelles
Digestion and Absorption of Lipids

Lipid Digestion

• Dietary lipids contain 98% triacylglycerols

(TAGs), which include fats and oils
 - saliva has no effect on digestion

- stomach:
• Normally two out of three fatty acids are
hydrolyzed * churning action – produces small fat droplets
(chyme)
• Small enough to be absorbed through intestinal
cell membranes * gastric lipases – hydrolyze some 10% TAGS

• Bile from liver form micelle - small intestine

* bile – solubilizes droplets

What happens to the Fatty Acids? * pancreatic lipases – produce

monoacylglycerols, which form fatty acid micelles
• Short- and medium-chain fatty acids
- intestinal cells: micelles repacked into TAGS which
– Enter portal blood directly from enterocytes form chylomicrons
– Bound to albumin in blood - lymphatic system: transport to bloodstream
– Oxidized in liver or elongated and used for -bloodstream: TAGs are hydrolyzed to free fatty acids
triglyceride formation
Triacylglycerol Storage and Mobilization
• Long-chain fatty acids (more than 12 C)
Adipose Tissue
– Form chylomicrons
• Largest cells in the body where the cytoplasm is
– Drain into the lymphatics via the lacteals
replaced with large TAG droplets
– Enter bloodstream at the thoracic duct
• Most cells have limited capability for
- Upstream from liver and low TAG storage but not adipose tissues
entry into the blood
• Located primarily beneath the skin, especially in
the abdominal region and vital organs

• In the intestinal cells, monoacylglycerols and • TAGs are stored in specialized cells
free fatty acids are repackaged to form TAGs called adipocytes found in adipose
• These new TAGs combine with membrane lipids tissue
(phospholipids and cholesterol) and water-
• Serves as an insulator against heat loss and
soluble proteins to form chylomicrons
protection against physical shock
o Chylomicrons: Lipoproteins that
transport TAGs from intestinal cells, via
the lymphatic system, to the
bloodstream
Structural Characteristics of Adipose Tissue 2. The glycerol phosphate is oxidized by NAD1 to
dihydroxyacetone phosphate, yielding NADH and H1 in
the process.

Glycolysis
---→

• Dihydroxyacetone phosphate then enters the

glycolysis pathway and is isomerized to
glyceraldehyde-3 phosphate and it now enters
it comprises about 20-25% of total body weight in
the TCA cycle
healthy individuals, the main function of adipose tissue
is to store energy in the form of lipids (fat). Beta Oxidation
Adipocytes (white, brown and beige) Thin extracellular Beta oxidation involves the process of sequentially
matrix consisting of reticular fibers. cleaving acetyl-CoA units from fatty acyl chains
There are two types of adipose tissue:

White adipose tissue - mainly found in adults what is it for?

Brown adipose tissue - mainly found in newborns • Beta-oxidation is the catabolic process by which
fatty acid molecules are broken down to
Glycerol Metabolism
generate acetyl-CoA, which enters the citric
Glycerol after entering the Bloodstream acid cycle, and NADH and FADH2, which are co-
enzymes used in the electron transport chain
• Taken to the liver or kidney and converted to
dihydroxyacetone phosphate in two steps: • Removal of acetyl CoA fragments from the ends
of fatty acids, also yielding NADH and FADH2 in
• Phosphorylation of primary hydroxyl
the process,. - ----- Acetyl CoA can enter citric
group of the glycerol
acid cycle--- NADH and FADH2 can enter the ETC
• Oxidization of secondary alcohol group
of glycerol to a ketone
where does it occur

• Tissues that can use fatty acids as energy

source, primarily muscle and liver

Glycerol Metabolism • Fatty acid activation occurs in the

cytosol
• The first step in glycerol utilization takes place
in the cytosol and is an activation step. • β-oxidation occurs in the mitochondria
and peroxisomes

• cytosol in prokaryotes and in the mitochondria

in eukaryotes to generate acetyl-CoA.
• Beta-oxidation is primarily facilitated by the
1. The body uses one ATP molecule to form glycerol-1- mitochondrial trifunctional protein, an enzyme
phosphate. complex associated with the inner
mitochondrial membrane, although very long
chain fatty acids are oxidized in peroxisomes.
 Acyladenylate mixed anhydride intermediate attacked
by the sulfhydryl group of CoA to form the thioester
WHAT ARE THE SUBSTRATES?
product
• Fatty Acids (ie. Palmitic acid and Linoleic acid)

Step 2: Transport of Fatty Acyl-CoA Across the

WHAT ARE THE PRODUCTS? Mitochondrial Membrane

• Acetyl-CoA, NADH, FADH2 ; Propionyl CoA (for • Transfer of acyl portion to carnitine
odd-numbered C fatty acids)
• Mediated by specific carrier protein

• Enzymes involved:
WHICH STEP IS RATE-LIMITING?
• carnitine palmitoyltransferases I and II
• Translocation of fatty Acyl CoA from the cytosol
• The inner mitochondrial membrane is
to the mitochondria
impermeable to fatty acids and a
Enzyme: Carnitine-palmitoyl transferase specialized carnitine carrier system operates to
transport activated fatty acids from cytosol to
mitochondria.
Steps Involved

1. Fatty acid activation

2. Transport of fatty acyl-CoA across the

mitochondrial membrane

3. Degradation of fatty acyl-CoA

Four reactions involved:

Step 1: Fatty acid activation
1. The acyl group of a cytosolic acyl-CoA is
• “priming” of fatty acids for reaction transferred to carnitine, thereby releasing the
• ATP-dependent acylation to form fatty acyl- CoA to its cytosolic pool. -> coA is released and
CoA catalyzed by acyl-CoA synthetases goes back to cytosol. Acyl will attach to
(thiokinases) carnitine palmitoyl transferase 1

2. The resulting acyl-carnitine is transported into

the mitochondrial matrix by the transport
system.

3. The acyl group is transferred to a CoA molecule

Site: cytosol. Takes place in the outer mitochondrial from the mitochondrial pool.
membrane
4. The product carnitine is returned to the cytosol.
Fatty acids react with CoA in the presence of ATP to
produce high-energy acyl CoA

ATP is converted to AMP Step 3: Degradation of Fatty Acyl-CoA

This process is for the fatty acid to be activated by • Four reactions repeatedly cleave two carbon
binding to coenzyme A units from the carboxyl end of the acyl CoA
molecule
Thiokinases are associated with either the endoplasmic
reticulum (ER) or the outer mitochondrial membrane
• This process is also called β-oxidation pathway the double bond is hydrated. An enzyme specifically
because the second carbon or beta carbon places the hydroxyl group on C-3, the beta carbon.
from the carboxyl end of the chain is oxidized.
Step 3: Oxidation
• Fatty acid must be repeatedly (fatty acid spiral)
oxidized to produce acetyl CoA, FADH2, and • This step requires NAD+ as a coenzyme. The two
NADH hydrogens and electrons removed are
transferred to the NAD+ to form NADH+ and H+.
• Oxidation → Hydration → Oxidation →
In the process, a secondary alcohol is oxidized
Thiolysis
to a ketone at the beta carbon.
• Each cycle yields acetyl CoA, NADH, FADH2 and • requires NAD1 as a coenzyme. The two
propionyl CoA (if odd-numbered carbon) hydrogens and electrons removed are
transferred to the NAD1 to form NADH 1 H1. In
• Fatty acid must be repeatedly (fatty acid spiral) the process, a secondary alcohol is oxidized to a
oxidized to produce acetyl CoA, FADH2, and ketone at the beta carbon.
NADH • Enzyme: b-hydroxyacyl-CoA dehydrogenase
• product: b-ketoacxyl-CoA

Step 1: oxidation:
Step 4: Thiolysis
• Hydrogen atoms are removed from the α and β
carbons, creating a double bond between these • Fatty acid chain is broken between the α and β
two carbon atoms carbons by reaction with a coenzyme A
• FAD is the oxidizing agent, and an FADH2 molecule.
molecule is the product • The result is an acetyl CoA molecule and a new
acyl CoA molecule that is shorter by two carbon
atoms than its predecessor

• Enzyme: acyl-coA dehydrogenase and oxidized

by FAD to form a double bond
• Product: trans-enoyl-CoA • the enzyme thiolase cleaves the terminal C2
• dehydrogenation; Step ①), two hydrogens are fragment (an acetyl-CoA) from the chain and
removed, creating a trans double bond between the rest of the molecule is bonded to a new
the alpha and beta carbons of the acyl chain. molecule of coenzyme A.
The hydrogens and electrons are picked up by
FADH2.

Step 2: Hydration

• A molecule of water is added across the trans

double bond, producing a secondary alcohol at
the β-carbon position

The cycle then starts again with the remaining acyl-CoA,

which is now two carbon atoms shorter. At each turn of
the cycle, one acetyl-CoA is produced.
Most fatty acids contain an even number of carbon Liver, kidney, heart – malate aspartate pathway
atoms. The cyclic spiral continues until it reaches the (normal)
last four carbon atoms. When this fragment enters the
cycle, two acetyl-CoA molecules are produced in the
fragmentation step. ATP Yield of Eicosanoid

• The beta oxidation of unsaturated fatty acids

proceeds in the same way. An extra step is
involved, in which the cis double bond is
isomerized to a trans bond, but otherwise the
spiral is nearly the same.

Beta Oxidation Unsaturated Fatty Acids Krebs Cycle = 1 ATP, 3 NADH, 1 FADH2

• Oxidation of unsaturated fatty acids requires

two additional steps compared to saturated • Acetyl CoA formed from β-oxidation pathway is
fatty acids further processed by the citric acid cycle
• Epimerase - Changes D configuration to an L • Adequate balance in carbohydrate and lipid
configuration metabolism is required
• Cis–trans isomerase - Produces a trans-(2,3) • Lipid–carbohydrate metabolism can be
double bond from a cis-(3,4) double bond disturbed by the following conditions:
• The b-oxidation of unsaturated fatty acids • Dietary intake is high in fat and low in
proceeds in the same way. An extra step is carbohydrates
involved, in which the cis double bond is
isomerized to a trans bond, but otherwise the • Diabetic conditions where the body cannot use
spiral is nearly the same. glucose properly

• Prolonged fasting conditions

ATP Yield of Palmitate Ketone Bodies and Ketogenesis

Ketone Bodies

• Ketone bodies are the water-soluble molecules

containing the ketone group that are produced
by the liver from fatty acids during periods of
low food intake, carbohydrate restrictive diets,
starvation, prolonged intense exercise,
alcoholism, or in untreated type 1 diabetes
mellitus.

16 c / Krebs Cycle = 1 ATP, 3 NADH, 1 FADH2

= 16/2= 8 acetyl -1 -> 7 NADH

Muscle and brain – glycerophosphate pathway

(naholdap)
 - Acetone, acetoacetic acid, beta-
hydroxybutyric acid
• Under low supply of oxaloacetate, the acetyl
CoA will be in excess (increased concentration)
• As a consequence, the excess acetyl CoA is
converted to ketone bodies

Ketogenesis
Step 3: Chain cleavage
• Involves the synthesis of ketone bodies from
HMG-CoA is cleaved to acetyl CoA and acetoacetate
acetyl CoA

• Primary site for this process is in the liver

mitochondria

• The three ketone bodies produced are:

— Acetoacetate

— β-hydroxybutyrate

— Acetone
Step 4: Hydrogenation

Acetoacetate is reduced to β-hydroxybutyrate

Step 1: First condensation
-acetone is least abundant ketone bodies
• Two acetyl CoA molecules combine to produce
acetoacetyl CoA, a reversal of the last step of
the β-oxidation pathway

• Enzyme: thiolase

• Product: acetoacetyl-CoA

Step 2: Second condensation

• Acetoacetyl CoA reacts with a third acetyl CoA

and water to produce 3-hydroxy-3-
methylglutaryl CoA (HMG-CoA) and CoA–SH
Fatty Acid Synthesis
• Enzyme: HMG-CoA synthase
Fatty Acids (FA) are Synthesized in the Liver and in
• Product: B-hydroxy-B-methylglutaryl-CoA Adipose Tissues with Dietary Glucose Serving as the
Major Source Of Carbon

A. Conversion of glucose to cytosolic Acetyl CoA

 B. Conversion of Acetyl CoA to Malonyl CoA

C. Fatty Acid Synthase Complex

D. Elongation of Fatty Acid

C. Fatty Acid Synthase Complex

• All intermediates in fatty acid synthesis are

Lipogenesis is the metabolic process through which linked to acyl carrier protein (ACP–SH)
acetyl-CoA is converted to triglyceride for storage in fat.
• ACP–SH can be regarded as a “giant CoA
The triglycerides in fat are packaged within cytoplasmic
molecule”
lipid droplets.
• Malonyl CoA is elongated by the FAS complex to
produce palmitate
A. Conversion of Glucose to Cytosolic
• Fatty acid formation is made efficient as all
Acetyl CoA
reactions for the process takes place within the
• Produced from the condensation of OAA to complex
Acetyl CoA inside the mitochondria from
• Large enzyme composed of 2 identical dimers
pyruvate.
• Each dimer possesses 7 catalytic activities and
• This is greatly influenced by insulin/glucagon
an acyl carrier protein (ACP)
ratio.
• FAS PURPOSE: process the fatty acid chain
• CoA is the starting material for lipogenesis
through 7 cycles to produce the 16-C product; 4
C's are introduced in the first cycle from Acetyl
CoA and Malonyl CoA; subsequent cycles 2 C
units are derived from Malonyl CoA following
the release of CO2

D. Elongation of Fatty Acid

B. Conversion of Acetyl CoA to Malonyl CoA

• Acetyl CoA is the starting material for

lipogenesis

• Acetyl CoA needed for lipogenesis is generated

in mitochondria and must first be transported
to the cytosol.

• Citrate–malate transport system helps transport

acetyl CoA to the cytosol indirectly.
Reaction 1: E. Termination

Condensation of Acetyl CoA and Malonyl CoA • Rounds of synthesis continue until a C16
palmitoyl group is formed.
Step 1: Condensation—where acetyl ACP and malonyl
ACP condense together to form acetoacetyl ACP • Palmitoyl-ACP is hydrolyzed by a thioesterase.

Reaction 2:

Reduction of Acetoacetyl ACP to 3-Hydroxyacetyl ACP

Step 2: Hydrogenation—where the keto group of the

acetoacetyl complex is reduced to alcohol by NADPH
Unsaturated Fatty Acid Biosynthesis

• To produce a double bond, molecular O2 is

needed

• In humans and animals, enzymes can only

introduce double bond between C4 and C5 and
between C9 and C10

• Consequence - Essential unsaturated fatty acids

linoleic (C18 with C9 and C12 double bonds) and
linolenic (C18 with C9, C12, and C15 double
bonds) cannot be biosynthesized

• Should come from diet (Plants have enzymes to

synthesize them)
Reaction 3:

Dehydration of 3-Hydroxyacetyl ACP to trans-2-enoyl

ACP Clinical Significance

Step 3: Dehydration—where water is removed from Enhanced lipogenesis is a characteristic feature of

alcohol to form an alkene cancer

• Tumor cell survival is influenced by

deregulated lipid biosynthesis
Reaction 4:
• Leads to a continuous supply of fatty
Reduction of trans-2-enoyl ACP to Butyryl ACP acids for membrane production of
Step 4: Hydrogenation—where hydrogen is added to highly proliferating cells
alkene 3 to form saturated butyryl ACP from NADPH • Lipids synthesized are also used for
energy and protein modification

• In the second round butyryl ACP condenses • Affects signal transduction and gene
with malonyl ACP to form a C6-B-ketoacyl ACP. expression

• Reduction, dehydration, and a second • Gene expression:

reduction convert the C6-B- ketoacyl ACP into a • - FASN overexpression
C6- acyl ACP, which is ready for a third round of
elongation. Metabolic anomalies arise when deregulation occurs in
lipogenesis.
 1. Obesity

2. Hypertriglyceridemia

3. Non-alcoholic fatty liver disease

Lipogenesis vs degradation of a fatty acids

• Cholesterol is an extremely important biological
Lipogenesis Degradation of a fatty molecule that has roles in membrane structure
acids as well as being a precursor for the synthesis of
the steroid hormones, the bile acids, and
Occurs in the cell cytosol Occurs in the vitamin D. Both dietary cholesterol, and that
mitochondrial matrix synthesized de novo, are transported through
the circulation in lipoprotein particles. The same
is true of cholesteryl esters, the form in which
A multi-enzyme complex Enzymes are not cholesterol is stored in cells. Due to its
called fatty acid synthase physically associated, important role in membrane function, all cells
catalyzes reactions and the reaction steps express the enzymes of cholesterol
are independent biosynthesis.

1. Acetyl-CoAs are converted to 3-hydroxy-3-

Intermediates are The carrier for fatty acid
methylglutaryl-CoA (HMG-CoA)
bonded to acyl carrier degradation is CoA
protein (ACP) 2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based

Dependent on the Dependent on FAD and
molecule, isopentenyl pyrophosphate (IPP)
reducing agent NADPH NAD+
4. IPP molecules are converted to squalene

5. Squalene is converted to cholesterol.

Cholesterol Synthesis

Cholesterol Cholesterol Synthesis

• Lipid, hydrophobic 1. Acetyl-CoAs are converted to 3-hydroxy-3-

methylglutaryl-CoA (HMG-CoA)
• Required precursor
2. HMG-CoA is converted to mevalonate
— Vitamin D

— Steroids

— Membrane stability

— Bile acids

— Most active production in:

3. Mevalonate is converted to the isoprene based

molecule, isopentenyl pyrophosphate (IPP)
 4. IPP molecules are converted to squalene

5. Squalene is converted to cholesterol

Overview of Cholesterol Synthesis

Acetyl CoA Acetoacetyl CoA

HMG-CoA
Synthase

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
2 NADPH
HMG-CoA
Reductase Rate Limiting Step

+
CoA + 2 NADP

Mevalonic Acid
3 ATP Mevalonate Pathway

6 Isopentenylpyrophosphate

Squalene

Lanoterol

Cholesterol