Lipids Metabolism -1

content - Metabolism of lipids:

•Triacylglycerol catabolism (Lipolysis -- breakdown)
•fatty acids biosynthesis (Lipogenesis)
•Cholesterol and phospholipids biosynthesis
• Ketones bodies biosynthesis (Ketogenesis)
• Ketones bodies breakdown (ketolysis)
•Lipoproteins metabolism
• Regulation and pathology of lipid metabolism
•Atherosclerosis
 Triacylglyceride Storage & Mobilization
• Storage of triacylglycerol
is in adipocytes
• Fatty acids stored
primarily as triacylglycerol
• Triacylglycerol is
hydrolyzed to release
fatty acids when needed.
 Triacylglyceride Storage & Mobilization –cont.

• TGs are delivered to adipose tissue in the form of

chylomicrons (small intestine) and VLDL (liver),
hydrolyzed by lipoprotein lipase into fatty acids and
glycerol, which are taken up by adipocytes.
• Also the access amount of free fatty acids are re-esterified
to TGs.
• TGs are stored in adipocytes.
 Lipolysis (breakdown)
• At low carbohydrate and insulin concentrations (during fasting),
TG hydrolysis is stimulated.

•This degradation of TAG in adipose tissue (lipolysis) is

catalyzed by hormone sensitive lipase (HSL).
This enzyme is activated by by epinephrine, nor
epinephrine, glucagon, and adrenocorticotropic hormone
and inhibited by insulin.
 Oxidation of Glycerol
• Glycerol is absorbed by the liver.

• Steps: phosphorylation, oxidation and isomerisation.

• Glyceraldehyde 3-phosphate is an intermediate in:

• glycolytic pathway
• gluconeogenic pathways
Isomerase
 ATP Generation from Glycerol Oxidation
• glycerol – glycerol 3-phosphate - 1 ATP
• glycerol 3-phosphate - dihydroxyacetone
phosphate 3ATP (1 NADH)

• glyceraldehyde 3-phosphate – pyruvate

5 ATP (1NADH + 2 ATP)

• pyruvate – acetyl CoA 3 ATP (1 NADH)

• acetyl CoA in Krebs cycle

12 ATP (3NADH + 1 FADH2 + 1GTP)

• Total 22 ATP
 Utilization of FA within the cell
•Plasma FFA are derived mainly from Lipolysis in adipose tissue
(pool -1) and portion of FFA is derived from degradation of VLDL
and chylomicrons by the action of the enzyme lipoprotein lipase
(pool-2) and small portion of absorption of dietary sources (small
and medium chain FA )
•Tissues take up FA from the blood to rebuild fats or to obtain
energy from their oxidation.
•Metabolism of FA is especially intensive in the liver.
•Free fatty acids (FFA) are transferred with albumin in the blood.
FA in blood → enter to the cell → in the cytoplasm FA are
converted to their CoA derivatives by enzyme acyl-CoA-
synthetase (ATP is consumed) → acyl-CoAs
Fatty acid + ATP + CoA Acyl-CoA + PPi + AMP
 Why Fatty Acids?
(For energy storage?)

• Two reasons:
– The carbon in fatty acids (mostly CH2) is
almost completely reduced (so its oxidation
yields the most energy possible).
– Fatty acids are not hydrated (as mono- and
polysaccharides ), so they can pack more
closely in storage tissues
 Fatty acids oxidation
β-oxidation of fatty acids
• substrate: - fatty acid acyl-CoA
• product: n acetyl-CoA, n NADH + H+, n FADH2
• function: gain of energy from fatty acids
• subcelullar location: matrix of mitochondria
• organ location: liver, heart, kidney, lungs, skeletal muscles and
other tissues with expection to CNS ,erythrocytes and adrenal
medulla
In cardiac muscle fatty acids are important fuel of respiration (80%
of energy derived from FA oxidation)
• regulatory enzyme: carnitine acyltransferase I
 Review Fatty acid

 Name  # Carbons: (saturation)

 Palmitate  16:0
 Stearate  18:0
 Palmitoleate  16:1 - cis at C9
 Oleate  18:1 - cis at C9
 Linoleate  18:2 - cis at C9 and C12
 Linolenate  18:3 - cis at C9, C12 & C15
 Fatty acids oxidation
β-oxidation of fatty acids
O

  C
4
3 1 O
2

fatty acid with a cis- 9

double bond

A 16-C fatty acid (Palmitic acid ) with numbering conventions is

shown.
Most naturally occurring fatty acids have an even number of carbon
atoms.
The pathway for catabolism of fatty acids is referred to as the b-
oxidation pathway, because oxidation occurs at the b-carbon (C-3).
Fatty acid activation: fatty acids in cytosol of the cell
(extramitochondrial) must be first activated so that they participate
metabolic path way .
The activation require energy which provided by ATP. In the presence
of ATP ,and coenzyme A ,the enzyme acyl- co-A synthetase
(Thiokinase) catalyze the conversion of FFA into an “active” FA acyl
co- A
Fatty acids must be esterified to Coenzyme A before they can undergo
oxidative degradation, be utilized for synthesis of complex lipids.
Acyl-CoA synthetase (Thiokinase) of ER & outer mitochondrial
membranes catalyze activation of long chain fatty acids, esterifying
them to coenzyme A.
This process is ATP-dependent, & occurs in 2 steps. There are different
Acyl-CoA Synthases for fatty acids of different chain lengths. 
Transport of Fatty acids into mitochondria
 Carnitine transport system

Fatty acids are activated on outer mitochondrial membrane ,

but oxidized in mitochondrial matrix
 β-oxidation of fatty acids

β-oxidation has 4 stages and generates NADH,

FADH2 and Acetyl CoA
Acetyl CoA is further oxidized in TCA cycle
 NADH, FADH2 in respiratory chain .
β-oxidation 4 steps are
repeated – each time 2
carbons are cleaved off
 β-oxidation may be defined as the oxidation of fatty acids
on the beta-carbon atom.
This results in the sequential removal of a two carbon
fragment, acetyl CoA .

Stages and tissues :

1- activation of fatty acids occurring in the cytosol
2- Transport of fatty acids into mitochondria
3- β-oxidation proper in the mitochondrial matrix (4 reaction )
 fatty acids are oxidized by most of the tissues in the body.
Brain ,erythrocytes , and adrenal medulla cannot utilized fatty
acids for energy requirement .
 β-oxidation proper
• Each cycle of β-oxidation , liberating a two
carbon unit – acetyl CoA , occurs in a sequence
of four reactions :

1. Oxidation
2. Hydration
3. Oxidation
4. Cleavage
1. Oxidation :
• Acyl CoA undergoes dehydrogenation by an FAD-
dependent flavoenzyme , acyl CoA dehydrogenase .
• A double bond is formed between α and β carbons (2, and
3 carbons)
2. Hydration :
• Enoyl Co A hydratase brings and hydration of double
bond to form β- hydroxyacyl Co A
3. Oxidation : β- hydroxyacyl Co A dehydrogenase
catalyses the second oxidation and degrades NADH
• The product formed is : β- ketoacyl Co A
4. Cleavage : The final reaction is the liberating of a2 carbon
fragment , acetyl CoA from acyl CoA.
• This occurs by a thiolytic cleavage catalysed by β-
ketoacyl CoA Thiolase (or Thiolase)
• NB: Thiol is a compound contains a carbon-bonded
sulfhydryl (R–SH) group .
•The new acyl CoA , containing two carbons less than the
original , reenters the β-oxidation cycle .
•The process continues till fatty acid is completely oxidized .
Cycles of β-oxidation
 Connections to Electron Transport and ATP.
One turn of the fatty acid spiral produces ATP from the
interaction of the coenzymes FAD (step 1) and NAD+ (step 3)
with the electron transport chain.
• Total ATP per turn of the fatty acid spiral is :

• Step 1 - FAD into e.t.c. = 2 ATP

Step 3 - NAD+ into e.t.c. = 3 ATP
Total ATP per turn of spiral = 5 ATP
• Example with Palmitic Acid = 16 carbons = 8 acetyl groups
• Number of turns of fatty acid spiral = 8-1 = 7 turns
• ATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.
• NET ATP from Fatty Acid Spiral = 35 ATP
 Summary

For complete degradation of palmitic acid 7 cycles are

required.

Degradation of palmitic acid (16 C) gives 129 ATP in

total .

Regulation of β-oxidation of FA:

Regulatory enzyme is carnitine acyltransferase I – it is

inhibited by malonyl-CoA (intermediate of FA
synthesis).
 Tutorial questions
How many "high energy" (~) bonds are utilized in activating the fatty
acid, by esterifying it to coenzyme A? (-)___2_____
How many times is the b-oxidation pathway repeated during
oxidation of a 12-C fatty acid? ____5_____ 
How many each of NADH___5___, FADH2___5___, and Acetyl
CoA__6____ are produced, per 12-carbon fatty acid, in the b-
oxidation pathway?
Oxidation of each acetyl CoA in Krebs cycle yields 3 NADH and one
FADH2 (from succinate), resulting in additional production of
____18___NADH and ____6___FADH2.
Thus the yield is a total of ___23____NADH and ___11____FADH2.
•In the respiratory chain, approx. 2.5 ~ bonds of ATP are produced
per NADH and 1.5 ~ bonds of ATP per FADH2 (electrons entering
the respiratory chain via coenzyme Q).

•Thus from reoxidation of NADH and FADH2 a total of ___74____

~ bonds of ATP are produced per 12-C fatty acid. 

•Add to this the ~P bonds of GTP produced in Krebs Cycle (one

GTP per acetyl-CoA) for a total of ____80___ ~P bonds produced.

•Summing input and output yields a total of __78_____ ~P  bonds

per 12-C fatty acid oxidized. Does fat yield more energy than
carbohydrate? ___YES____ 
 energy, lipoproteins, Hormone sensitive lipase, Albumin

• Fill gapes please :

• …………….. releases fatty acids from intracellular TAG
stores
• Lipoprotein lipases releases fatty acids from ………..
into blood stream
• Fatty acids enter blood stream, kept soluble by binding
to………..
• Intracellular catabolism of fatty acids to produce
 CoAs,2 membranes, Mitochondrial matrix, acyl-carnitine ,
Cβ = β-oxidation
• degradation of fatty acid through oxidation of ………….in
…………………..
• In β-oxidation FA need to cross …………….to reach
matrix not as …………but as ………………….
 Energy balance of β-oxidation
• for C16 Palmitic acid: ……..rounds of β-oxidation - >
……. x acetyl-CoA
• Each round of β-oxidation produces:
• 1 NADH -> …… ATP
• 1 FADH2 -> …… ATP
• 1 acetyl-CoA -> TCA (1) GTP, (3) NADH, (1)FADH2
(respiration only !)
• OVERALL NET YIELD: .......ATP per C......