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

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

Lipid Digestion

• Dietary lipids contain 98% triacylglycerols

(TAGs), which include fats and oils

• Normally two out of three fatty acids are
hydrolyzed
• Small enough to be absorbed through intestinal
cell membranes
• Bile from liver form micelle
What happens to the Fatty Acids?
• Short- and medium-chain fatty acids
– Enter portal blood directly from enterocytes
– Bound to albumin in blood
– Oxidized in liver or elongated and used for
triglyceride formation
• Long-chain fatty acids (more than 12 C)
– Form chylomicrons
– Drain into the lymphatics via the lacteals
– Enter bloodstream at the thoracic duct
- Upstream from liver and low
entry into the blood
• In the intestinal cells, monoacylglycerols and
free fatty acids are repackaged to form TAGs
• These new TAGs combine with membrane lipids
(phospholipids and cholesterol) and water-
soluble proteins to form chylomicrons
o Chylomicrons: Lipoproteins that
transport TAGs from intestinal cells, via
the lymphatic system, to the
bloodstream
- saliva has no effect on digestion
- stomach:
* churning action – produces small fat droplets
(chyme)
* gastric lipases – hydrolyze some 10% TAGS
- small intestine
* bile – solubilizes droplets
* pancreatic lipases – produce
monoacylglycerols, which form fatty acid micelles
- intestinal cells: micelles repacked into TAGS which
form chylomicrons
- lymphatic system: transport to bloodstream
-bloodstream: TAGs are hydrolyzed to free fatty acids
Triacylglycerol Storage and Mobilization
Adipose Tissue
• Largest cells in the body where the cytoplasm is
replaced with large TAG droplets
• Most cells have limited capability for
TAG storage but not adipose tissues
• Located primarily beneath the skin, especially in
the abdominal region and vital organs
• TAGs are stored in specialized cells
called adipocytes found in adipose
tissue
• Serves as an insulator against heat loss and
protection against physical shock
Structural Characteristics of Adipose Tissue
it comprises about 20-25% of total body weight in
healthy individuals, the main function of adipose tissue
is to store energy in the form of lipids (fat).
Adipocytes (white, brown and beige) Thin extracellular
matrix consisting of reticular fibers.
There are two types of adipose tissue:
White adipose tissue - mainly found in adults
Brown adipose tissue - mainly found in newborns
Glycerol Metabolism
Glycerol after entering the Bloodstream
• Taken to the liver or kidney and converted to
dihydroxyacetone phosphate in two steps:
• Phosphorylation of primary hydroxyl
group of the glycerol
• Oxidization of secondary alcohol group
of glycerol to a ketone
Glycerol Metabolism
• The first step in glycerol utilization takes place
in the cytosol and is an activation step.
1. The body uses one ATP molecule to form glycerol-1-
phosphate.
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
the TCA cycle
Beta Oxidation
Beta oxidation involves the process of sequentially
cleaving acetyl-CoA units from fatty acyl chains
what is it for?
• Beta-oxidation is the catabolic process by which
fatty acid molecules are broken down to
generate acetyl-CoA, which enters the citric
acid cycle, and NADH and FADH2, which are co-
enzymes used in the electron transport chain
• Removal of acetyl CoA fragments from the ends
of fatty acids, also yielding NADH and FADH2 in
the process,. - ----- Acetyl CoA can enter citric
acid cycle--- NADH and FADH2 can enter the ETC
where does it occur
• Tissues that can use fatty acids as energy
source, primarily muscle and liver
• Fatty acid activation occurs in the
cytosol
• 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
mitochondrial trifunctional protein, an enzyme
complex associated with the inner
mitochondrial membrane, although very long
chain fatty acids are oxidized in peroxisomes.

WHAT ARE THE SUBSTRATES?
• Fatty Acids (ie. Palmitic acid and Linoleic acid)
WHAT ARE THE PRODUCTS?
• Acetyl-CoA, NADH, FADH2 ; Propionyl CoA (for
odd-numbered C fatty acids)
WHICH STEP IS RATE-LIMITING?
• Translocation of fatty Acyl CoA from the cytosol
to the mitochondria
Enzyme: Carnitine-palmitoyl transferase
Steps Involved
1. Fatty acid activation
2. Transport of fatty acyl-CoA across the
mitochondrial membrane
3. Degradation of fatty acyl-CoA
Step 1: Fatty acid activation
• “priming” of fatty acids for reaction
• ATP-dependent acylation to form fatty acyl-
CoA catalyzed by acyl-CoA synthetases
(thiokinases)
Site: cytosol. Takes place in the outer mitochondrial
membrane
Fatty acids react with CoA in the presence of ATP to
produce high-energy acyl CoA
ATP is converted to AMP
This process is for the fatty acid to be activated by
binding to coenzyme A
Thiokinases are associated with either the endoplasmic
reticulum (ER) or the outer mitochondrial membrane
Acyladenylate mixed anhydride intermediate attacked
by the sulfhydryl group of CoA to form the thioester
product
Step 2: Transport of Fatty Acyl-CoA Across the
Mitochondrial Membrane
• Transfer of acyl portion to carnitine
• Mediated by specific carrier protein
• Enzymes involved:
• carnitine palmitoyltransferases I and II
• The inner mitochondrial membrane is
impermeable to fatty acids and a
specialized carnitine carrier system operates to
transport activated fatty acids from cytosol to
mitochondria.
Four reactions involved:
1. The acyl group of a cytosolic acyl-CoA is
transferred to carnitine, thereby releasing the
CoA to its cytosolic pool. -> coA is released and
goes back to cytosol. Acyl will attach to
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
from the mitochondrial pool.
4. The product carnitine is returned to the cytosol.
Step 3: Degradation of Fatty Acyl-CoA
• Four reactions repeatedly cleave two carbon
units from the carboxyl end of the acyl CoA
molecule
• This process is also called β-oxidation pathway
because the second carbon or beta carbon
from the carboxyl end of the chain is oxidized.
• Fatty acid must be repeatedly (fatty acid spiral)
oxidized to produce acetyl CoA, FADH2, and
NADH
• Oxidation → Hydration → Oxidation →
Thiolysis
• Each cycle yields acetyl CoA, NADH, FADH2 and
propionyl CoA (if odd-numbered carbon)
• Fatty acid must be repeatedly (fatty acid spiral)
oxidized to produce acetyl CoA, FADH2, and
NADH
Step 1: oxidation:
• Hydrogen atoms are removed from the α and β
carbons, creating a double bond between these
two carbon atoms
• FAD is the oxidizing agent, and an FADH2
molecule is the product
• Enzyme: acyl-coA dehydrogenase and oxidized
by FAD to form a double bond
• Product: trans-enoyl-CoA
• dehydrogenation; Step ①), two hydrogens are
removed, creating a trans double bond between
the alpha and beta carbons of the acyl chain.
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 double bond is hydrated. An enzyme specifically
places the hydroxyl group on C-3, the beta carbon.
Step 3: Oxidation
• This step requires NAD+ as a coenzyme. The two
hydrogens and electrons removed are
transferred to the NAD+ to form NADH+ and H+.
In the process, a secondary alcohol is oxidized
to a ketone at the beta carbon.
• requires NAD1 as a coenzyme. The two
hydrogens and electrons removed are
transferred to the NAD1 to form NADH 1 H1. In
the process, a secondary alcohol is oxidized to a
ketone at the beta carbon.
• Enzyme: b-hydroxyacyl-CoA dehydrogenase
• product: b-ketoacxyl-CoA
Step 4: Thiolysis
• Fatty acid chain is broken between the α and β
carbons by reaction with a coenzyme A
molecule.
• The result is an acetyl CoA molecule and a new
acyl CoA molecule that is shorter by two carbon
atoms than its predecessor
• the enzyme thiolase cleaves the terminal C2
fragment (an acetyl-CoA) from the chain and
the rest of the molecule is bonded to a new
molecule of coenzyme A.
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
atoms. The cyclic spiral continues until it reaches the
last four carbon atoms. When this fragment enters the
cycle, two acetyl-CoA molecules are produced in the
fragmentation step.
• 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
• Oxidation of unsaturated fatty acids requires
two additional steps compared to saturated
fatty acids
• Epimerase - Changes D configuration to an L
configuration
• Cis–trans isomerase - Produces a trans-(2,3)
double bond from a cis-(3,4) double bond
• The b-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.
ATP Yield of Palmitate
16 c / Krebs Cycle = 1 ATP, 3 NADH, 1 FADH2
= 16/2= 8 acetyl -1 -> 7 NADH
Muscle and brain – glycerophosphate pathway
(naholdap)
Liver, kidney, heart – malate aspartate pathway
(normal)
ATP Yield of Eicosanoid
Krebs Cycle = 1 ATP, 3 NADH, 1 FADH2
• Acetyl CoA formed from β-oxidation pathway is
further processed by the citric acid cycle
• Adequate balance in carbohydrate and lipid
metabolism is required
• Lipid–carbohydrate metabolism can be
disturbed by the following conditions:
• Dietary intake is high in fat and low in
carbohydrates
• Diabetic conditions where the body cannot use
glucose properly
• Prolonged fasting conditions
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.
 - 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
Lipogenesis
Occurs in the cell cytosol
A multi-enzyme complex
called fatty acid synthase
catalyzes reactions
Intermediates are
bonded to acyl carrier
protein (ACP)
Dependent on the
reducing agent NADPH
Cholesterol Synthesis
Cholesterol
• Lipid, hydrophobic
• Required precursor
— Vitamin D
— Steroids
— Membrane stability
— Bile acids
— Most active production in:
• Cholesterol is an extremely important biological
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 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
Enzymes are not cholesterol is stored in cells. Due to its
physically associated, important role in membrane function, all cells
and the reaction steps express the enzymes of cholesterol
are independent biosynthesis.
1. Acetyl-CoAs are converted to 3-hydroxy-3-
The carrier for fatty acid
methylglutaryl-CoA (HMG-CoA)
degradation is CoA
2. HMG-CoA is converted to mevalonate
3. Mevalonate is converted to the isoprene based
Dependent on FAD and
molecule, isopentenyl pyrophosphate (IPP)
NAD+
4. IPP molecules are converted to squalene
5. Squalene is converted to cholesterol.
Cholesterol Synthesis
1. Acetyl-CoAs are converted to 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA is converted to mevalonate
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