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BC 368
Biochemistry of the Cell II
Fatty Acid Catabolism, Chapter 17
April 21, 2015
Overview of Lipid Catabolism
Triglycerides account for ~83% of our stored
energy
Mobilized slower than carbs and only
aerobically
Principal fuel for many organs (e.g., heart,
liver)
More energy per gram than carbs (9 kcal vs. 4)
Transport of Lipids
Nonpolar lipids need
to be escorted through
the bloodstream via
lipoprotein complexes.
Chylomicrons carry dietary
lipids to tissues
VLDLs carry lipids synthesized
in liver to tissues
LDLs carry cholesterol to tissues
HDLs carry cholesterol to liver
from tissues
Absorption of Dietary Fats
Dietary lipids must be emulsified and
packaged for transport in the bloodstream
Bile salts are made
from cholesterol in
the liver; stored in
gall bladder
taurocholic
acid
Absorption of
Dietary Fats
Step 1:
emulsification by
bile salts and
hydrolysis by
lipases
Absorption of
Dietary Fats
Step 2: packaging
for transport
Absorption of
Dietary Fats
Step 2: packaging
for transport
Absorption of
Dietary Fats
Step 3: hydrolysis
and entry into
target tissues
Mobilization of Fat Stores
Hormone (glucagon
or epinephrine) binds
to fat cell receptor,
activating protein
kinase A
Phosphorylation
activates lipase and
perilipin, triggering
release of fatty acids
Fate of Triglyceride Products
Fate of Triglyceride Products
Back to the Matrix!
Activation of Fatty Acids by CoA
Fig 17-5
Activation of Fatty Acids by CoA
Fig 17-5
Role of carnitine
Fig 17-6
Chemistry of Fat Catabolism
1904 classic experiment
Fed to dogs
1875-1946
Overview of β-Oxidation
Fatty acids are
broken down 2-carbon
units at a time, starting
at the carboxyl end.
Pieces are released
as acetyl-CoA.
Fig 17-7
Overview of  oxidation
Reaction Steps
Oxidation
Hydration
Oxidation
Cleavage
Fig 17-8
Reaction 1: Oxidation
Three isozymes of
acyl-CoA
dehydrogase:
Long chain (12-18C)
Medium chain (4-14C)
Short chain (4-8C)
Fig 17-8
Akee
(Blighia sapida)
“Pear-shaped fruit, with several moderate lobes
and a red to yellow waxy skin. The skin, unripe
fruit, and seeds are poisonous. The yellow, fleshy
portion surrounding the aril is edible and has a
nutty flavor.”
http://www.tradewindsfruit.com/akee.htm
“Down at the market you
can hear
Ladies cry out while on their
heads they bear
Akee, rice, salt fish are
nice,
And the rum is fine any time
of year…”
Jamaica Farewell
hypoglycin A
“Down at the market you
can hear
Ladies cry out while on their
heads they bear
Akee, rice, salt fish are
nice,
And the rum is fine any time
of year…”
Jamaica Farewell
hypoglycin A
Electron-Transfer Flavoprotein (ETF)
FADH2 reducing
equivalents are
passed to ElectronTransfer Flavoprotein
(ETF), which leads to
Q via an
oxidoreductase
Fig 19-8
Reaction 2:
hydration
Fig 17-8
Reaction 3:
oxidation
Fig 17-8
Reaction 4:
thiolytic cleavage
Fig 17-8
The synthetic compound shown
here is a fat substitute.
a) What are the two molecular components of this
compound and how does it compare to a triglyceride?
b) This compound is not digested. Why not?
c) Given the indigestibility of this compound, what is a
potential problem for consumers?
d) This compound has been shown to deplete nutrients
such as vitamin A and carotenoids. Why?
For more information, see www.american.edu/TED.olestra.htm
Oxidation of Unsaturated Fats
Double bonds are
always cis.
An isomerase is
needed to convert
the cis double bond
to the appropriate
trans intermediate.
Fig 17-10
Polyunsaturated Fats
Both an
isomerase
and a
reductase
are
necessary.
Polyunsaturated Fats
Some polyunsaturated fats are “essential”
building blocks for signaling molecules such
as the prostaglandins, thromboxanes, and
leukotrienes.
Essential fatty acid families
ω-3 family
ω-6 family
H3C
C18:2 ω-6
COOH
Linoleic
H3C
C18:3 ω-3
C20:4 ω-6
H3C
COOH
Arachidonic
-Linolenic
• Flaxseed Oil
• Canola Oil
• Soybean Oil
• Corn Oil
• Safflower Oil
• Sunflower Oil
H3C
COOH
C20:5 ω-3
H3C
C22:6 ω-3
COOH
Eicosapentaenoic
(EPA)
COOH
Docosahexaenoic
(DHA)
• Oily Fish
• Fish Oil Capsules
A high fish diet correlates to lower acute MI
(sudden heart attack) rates
WEM Lands, Fish and Human Health, 1986
Historic incidence of heart disease in Oslo
Acta Med Scand
1981;210:245-8
Dietary Changes: Margarine, butter, CLO decreased from 159 to 79 g/d. Oily
fish intake increased from 99 to 292 g/d.
Double-blind placebo-controlled study: giving
GISSI
Prevenzione:
Time Course
DHA -and
EPA to people
afterofaClinical
heartEvents
attack
>11,300 post-MI patients were given usual care with or
without 850 mg EPA+DHA (Omacor) for 3.5 years
Probability
Total
mortality
reduced
by 28%
(p=0.027)
1.00
n-3 PUFA
Control
0.99
0.98
0.97
0.59 (0.36–0.97)
p=0.037
0.72 (0.54–0.96)
p=0.027
0.96
0.95
Days 0
30
60
90
120 150 180 210 240 270 300 330 360
1.00
Probability
100 g serving0.99
of farmed salmon = 2.147 g DHA/EPA
Sudden
death
0.98
0.47 (0.22–0.99)
n-3 PUFA
reduced
p=0.048
0.97
0.53 (0.32–0.88)
Control
p=0.0136
by 47%
0.96
(p=0.0136)
0.95
Marchioli
R, et60
al. Circulation
2002;105:1897-1903.
0
Days
30
90 120 150
180 210 240 270 300 330 360
What do EPA and DHA do to lower the risk for
heart disease?
•Lower heart rate (Harris WS et al. Am J Cardiol 98:1393-1995,
2006)
•Prevent ventricular tachyarrhythmias
(Billman GE et
al. Proc Natl Acad Sci USA 1994;91:4427-4430.)
•Lower blood pressure (Geleijnse et al., J. Hypertens., 2002;
20:1493-9)
•Lower platelet function
Oxidation of Odd-Chain Fats
Propionyl-CoA is
the last piece
released.
Propionyl-CoA
undergoes
conversion to
succinyl-CoA, which
enters TCA.
Fig 17-11
Vitamin B12
Dorothy Crowfoot Hodgkin
(1910-1994)
Box 17-2
Vitamin B12
Dorothy Crowfoot Hodgkin
(1910-1994)
Box 17-2
Nobel prize winners of 1964 (from left
to right): C.H. Tauns, A.M. Prokhorov,
N.G. Basov (all in physics), D.
Crowfoot-Hodgkin, K.E. Bloch, and F.
Lynen
Very Long or Branched Chain
Predominantly in the
peroxisomes.
Similar, but not
identical, chemistry,
using several
auxiliary enzymes.
Very Long or Branched Chain
Defects can lead to
serious diseases such as Xlinked
Adrenoleukodystrophy.
Control
Fig 17-13
Ketone bodies
Made in the
mitochondrial
matrix of liver
cells.
Fig 17-21
Ketone Bodies
Ketone Bodies
Fig 17-19
Ketone Bodies
Alcoholic Ketoacidosis
“Forensic pathologists are familiar with alcohol
abusers, who are found dead and in whom the
cause of death cannot be ascertained. In order to
examine the possible role of ketoacidosis for the
cause of death in this group of alcohol abusers,
the concentrations of ketone bodies were
determined in post-mortem blood specimens…”
Thomsen JL, Felby S, Theilade P, Nielsen E. (1995) Alcoholic ketoacidosis
as a cause of death in forensic cases. Forensic Sci Int. 75, 163-71.
Alcoholic Ketoacidosis
Thomsen JL, Felby S, Theilade P, Nielsen E. (1995) Alcoholic ketoacidosis
as a cause of death in forensic cases. Forensic Sci Int. 75, 163-71.