b-Oxidation of fatty acids

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Transcript b-Oxidation of fatty acids

IV: Mitochondrial function (e.g. hepatocytes)
1) citric acid cycle as an energy source
a) pyruvate or a-ketoglutarate
dehydrogenase
b) lipoic acid therapy
2) the respiratory chain as an energy
source
3) oxidative phosphorylation and
uncouplers
4) membrane transporters and shuttles
a) cytosolic NADH oxidation
b) acetyl CoA (NADPH export)
c) transport systems in the mitochondria
d) gluconeogenesis and glucose
transport
5) mitochondrial diseases and treatment
a) creatine therapy
b) coenzyme Q10 therapy
6) b-oxidation of fatty acids as an energy source
a) starvation/diabetes/endstage renal disease
b) carnitine therapy
c) ketogenic diet therapy
d) drug induced fatty liver and NASH
e) alcohol induced fatty liver and ASH
7) hepatic detoxification of
a) monoamines
b) alcohols
c) toluene
8) hemoprotein mediated diseases
a) rhabdomyolysis
b) kernicterus
9) Heme biosynthesis & porphyria
a) Heme biosynthesis
b) Porphyria
c) Oxidative degradation of heme to bilirubin
10) Nitrogen metabolism
a) N-catabolism of amino acids
b) N-catabolism of purines
1
1. CITRIC ACID CYCLE AS
AN ENERGY SOURCE
A) Pyruvate or a-ketoglutarate dehydrogenase
Requires Thiamine (Vit B1) and lipoic acid
B) Lipoic acid therapy
2
An overview of the citric acid cycle
Stryer
3
Acetyl CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O 
2 CO2 + 3 NADH + FADH2 + GTP + 2H+ + CoA
toxic!
120uM plasma citrate
complexes Fe
4
Pyruvate dehydrogenase complex
.
Babies born with mitochondrial diseases usually have cytochrome deficiencies but some
have low pyruvate dehydrogenase E1 that causes lactic acidosis . Therapy includes
thiamine (B1) or CoQ suppl, dichloroacetate or a ketogenic diet.
Pyruvate decarboxylase (pyruvate to OAA)inhibited by branched chain aminoacids that
accumulate in maple syrup disease, inborn error of metabolism.
5
Pyruvate dehydrogenase complex
R
CoA
O
O
COO-
Thiamine
pyrophosphate
(TPP)
O
R
S
L
SH
R
E2
E1
OH
TPP
SH
As(III) POISON
S
Lipoamide
SH
L
Stryer Fig. 20-12.
Summary of the reactions
catalyzed by the pyruvate
dehydrogenase complex.
L. refers to the lipoyl group.
CoA
L
L
R
S
SH
S
CO2
SH
As
SH
FADH2
NAD
E3
+
FAD
Arsenite
complex
NADH + H+
Pyruvate + CoA + NAD+  acetyl CoA + CO2 + NADH
(Thiamine (Vitamin BI) required)
6
Lipoic acid (thioctic acid) therapy
•
•
•
Scavenges reactive oxygen and nitrogen oxide species
restores other cellular antioxidants
decreases oxidative stress toxicity
• prevents diabetes complications, cataracts and alcoholic liver
damage
• prevents Cis Pt chemotherapy induced nephrotoxicity,
hypertension and aging in rats
Free Rad. Biol. Med. 24, 1023-39 (1998).
7
The citric acid cycle is a source of biosynthetic precursors
Glucose
Pyruvate
ATP, CO2
Phosphoenolpyruvate
Acetyl CoA
ADP, Pi
Amino
acids
Oxaloacetate
Succinyl
CoA
Porphyrins
Citrate
Stryer Fig. 20-17.
Biosynthetic roles of the
citric acid cycle.
Intermediates drawn off
for biosyntheses are
replenished by the
formation of oxaloacetate
from pyruvate.
(Anaplerotic)
aketoglutarate
Amino
acids
8
Control of the
citric acid cycle
Stryer Fig. 20-22.
Control of the
citric acid cycle and
the oxidative
decarboxylation of
pyruvate: * indicates
steps that require an
electron acceptor
(NAD+ or FAD) that
is regenerated by the
respiratory chain.
9
2. THE RESPIRATORY CHAIN
AS AN ENERGY SOURCE
10
The mitochondrial respiratory chain
NADH
Diagram of a mitochondrion
FMNH2
complex I
NADH-Q
reductase
2Fe-2S
4Fe-4S
Q
FADH2
in flavoproteins
succinate:Q reductase
(complex II)
complex III Cytochrome
reductase
Chemiosmotic theory of oxidative phosphorylation
cyt c
complex IV Cytochrome
oxidase
O2
Sequence of electron
carriers in the
respiratory chain
11
O
H3C
C
H3C
C
H
C
C
H
C
C
N
C
C
N
N
O
NH
C
CH2
e- +
+
C
H3C
C
C
H
C
C
H
N
C
C
N
N
O
NH
C
e- +
CH2
H
O
+
H3C
C
H3C
C
H
H
C
C
H
C
C
H
N
C
CH
N
CH2
H
C
OH
H
C
OH
H
C
OH
H
C
OH
H
C
OH
H
C
OH
H
C
OH
H
C
OH
H
C
OH
a v i
n
CH2O PO3
m
2-
o n o n u c l Se eo mt i i d qe u i
( F M
N )
n o n e
i
C
N
H
CH2OPO32F l
O
H3C
H
C
NH
C
O
CH2O PO32n t e r m
e d i a t e
R e d u c e d
f l a v
)
2
Iron-sulfur complexes
The reduction of flavin mononucleotide (FMN) to FMNH2 proceeds through a
semiquinone intermediate
Molecular models of iron-sulfur complexes: iron = red; cysteine sulfur = yellow;
12
inorganic sulfur = green
NADH coenzyme Q reductase: complex I
FM
N
NADH
NAD+
eQ
R
O
FM
NH2
x QH2
N
A
D
O
O
O H
C
H
3
CO
C
C
H
3
CO
C
C
C
CH
CH
3
( C H 2C
H
C
-
e
3
CH
2
)
10
+
C
H
3
CO
C
H
3
CO
C
H
e-
+
C
CH
C
R
+
+
C
3
C
H 3C O
C
H 3C O
C
C
C
C
O
OH
C
(
1
o
U
0
e
B
S
I
O H
n
I
eR
n
z
Q
m
t
The reduction of ubiquinone to ubiquinol proceeds through a semiquinone
anion intermediate.
13
Model of NADH-Q reductase
Stryer Fig 21-9
14
Q:Cytochrome c reductase (Complex III)
Q
cyt b (+2)
QH
Fe-S(+2)
cyt c1(+3)
cyt c(Fe+2)
QH
cyt b (+3)
QH2
Fe-S(+3)
cyt c1(+2)
cyt c(Fe+3)
Stryer p. 537
cytochrome c reductase
Stryer Fig. 21-11
Model of a portion of
Q: cytochrome c reductase
15
Cytochrome oxidase (Complex IV)
Lodish Fig. 17-30
16
Electron transport can be
blocked by specific inhibitor
poisons
NADH
NADH-Q
Reductase
QH2
Blocked by
rotenone and
amytal
Cytochrome b
Blocked by
antimycin
Cytochrome c1
Sites of action of some
inhibitors of electron
transport
Cytochrome c
Cytochrome Oxidase
Blocked by
CN- , N3 -, and CO
O2
17
Cytochrome C - catalytic site
CH3
+
R C
CH2
HS C
R '
R C
S C
R '
H
H2
C y s t e i n e
r e s iH d u e H2
V i n y l
g r o u p
o f
t h e
p r o t e Ti hn i o e t h e r
o f
t h e
h e m
e
The heme in cytochromes c and c1 is
covalently attached to 2 cysteine side chains
by thioether linkages
The iron atom of the heme group in
cytochrome c is bonded to a methionine
18
sulfur atom and a histidine nitrogen atom
l
Spectroscopic characteristics of cytochrome c
Http://www.princeton.edu/~macase/cytochrome_c.html
19
Evolutionary Tree of Cytochrome C
20
Cytochrome C - soluble NOT membrane bound
1. 26/104 amino acids residues have been invariant for > 1.5 x 109 years.
2. Met 80 and His 18 - coordinate Fe.
3. 11 residues from number 70 - 80 lining a hydrophobic crevice have
remained virtually unchanged throughout all cytochrome c regardless
of species or even kingdom.
4. A number of invariant arginine and lysine clusters can be found on
the surface of the molecule.
Cytochrome c has a dual function in the cell. Electron transport for ATP
production AND the major cause of most programmed cell death
(apoptosis) is initiated by the release of cytochrome c into the cytosol!
21
Origin of mitochondria: the endosymbiont hypothesis
The endosymbiont hypothesis suggests that mitochondria have evolved
from anaerobic bacteria which were phagocytosed by eukaryote cells
at the time oxygen appeared on earth,
Similarities between mitochondria and bacteria include the presence of:
• cardiolipin
•transporters
• ribosomes
• circular RNA and DNA
Therefore mitochondria protein synthesis should be inhibited by:
• TETRACYCLINE
• CHLORAMPHENICOL.
E.g. The extensive use of these drugs can inhibit
1. Bone marrow mitochondrial protein synthesis leading to a
decline in the production of white or red cells.
2. Intestinal epithelial cells causing them to cease dividing.
22
3. OXIDATIVE
PHOSPHORYLATION AND
UNCOUPLERS
23
Oxidative phosphorylation
24
Uncouplers:
Physiological use of uncoupling
oxidative phosphorylation
Brown fat which is very rich
in mitochondria/chloroplast
supply heat for newborns,
hibernating animals, flowering
plants. Thermogenin is a 33Kd
protein which uncouples
mitochondria to generate heat.
thermogenin
25
MATRIX
CYTOSOL
pH = 7
Uncouplers of
oxidative
phosphorylation
O
H+
pH = 8
H+
OH
NO2
OH
O
NO2
NO2
NO2
NO2
NO2
NO2
NO2
2,4 - Dinitrophenol
ADP
H+
H+
ATP
Valinomycin
OO+ O
OK
OO
i.e. six valine residues
K+
Loss of electromotive force.
Energy used for K+,Na+ transport
and not for the production of ATP
Gramicidin 15 amino acids long
which forms a transmembrane
channel for Na+ entry into the
matrix.
Na+
Na+
26
a - ketoglutarate
O
2 level
Oligomycin
(inhibits ATPase)
ADP
in medium
O
Oligomycin however is
an ATPase inhibitor.
a - ketoglutarate
2 level
Oxygen electrode shows
DNP is a protonophore
(short circuits proton
gradient) & markedly
increases oxygen uptake
causing heat without
ATP formation.
in medium
2,4 - dinitrophenol
a - ketoglutarate
ADP
ADP
2 level
O
in medium
Coupled control cells
Peter Mitchell 1978
Nobel Prize
ATP
27
Time
4.Mitochondrial MEMBRANE
TRANSPORTERS
A) Cytosolic NADH oxidation
B) Acetyl CoA (NADPH export)
C) Transport systems in the mitochondria
D) Gluconeogenesis and glucose transport
28
Compartmentalization
of the major pathways
of metabolism
29
a) Cytosolic NADH oxidation: membrane transporters glycerol
phosphate shuttle (Bucher shuttle)
30
Vit.B6 requd. for Malate-aspartate shuttle
NADH can’t permeate mitochondrial
membrane but cytosol NADH must be
oxidised by mitochondria to sustain
glycolysis
Vitamin B6
31
b) Acetyl CoA/NADPH export to cytosol for fatty acid synthesis/
drug metabolism
G
l
u
c
o
s
e
C y t
P
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u
v
a
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C
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t S y y l n
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a
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+
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r a t
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t C h o a As
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ca
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s5
eb
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to
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M
CO2
ADP
m
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ATP
a
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NADP+
e
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N ADPH
CO2
T
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P
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p
n
l
h NADPH
o s
f
a
o
y mr
em s
z
i
p
h
a
P32 a
Isocitrate as an NADPH shuttle for drug metabolism
G
l
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c
o
s
e
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y
r
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v
a
t
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O
x
F
o
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NAD+
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NADH
M
A
C
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t
n
a
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c
C
H C
a
o
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i
A
C Y T O
R eI A L
t
N aD
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t
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R I
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D
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L NAD+
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S
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T
C I
a
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i
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c
C
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e
a-
as t o ec
i
t
r
a
t
NADP+
r
a t
e
i
s
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o
g e
n ca i s t e r
d
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h
y
d
r
o
NADPH
a
g
CO 2
k
e
t
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g
la-
uk t e at r o ag t l
eu
t
NAD+
n
A
y
l
P
D
4
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5
U
0
G
c
a
M
CO2
33
c) Transport
systems in the
mitochondria
Pyruvate transporter inhibited
by hydroxycinnamate
Malate transporter inhibited
by butylmalonate
Harper’s
Biochemistry.
34
d) Gluconeogenesis
and glucose export
by the liver !
Mitochondria/ cytosolic enz.,
& 6 ATP,2NADH required by
pyruvate carboxylase, PEP
carboxykinase, Pglycerate
kinase,GAPDH for
2pyruvateglucose
35
Glucagon 51aa & Insulin 29aa
• Pancreas synthesises both peptide hormones
• Glucagon hepatocyte receptors signals glycogenolysis
(glycogen breakdown to glucose then increases
gluconeogenesis pyruvate -- glucose)
• Drugs. Dipeptidyl peptidase-4 inhibitor (Januvia, new anti
type 2 diabetes) increases incretin , a GI hormonal peptide
inhibitor of glucagon which lowers plasma glucose.
• Metformin,major antidiabetic but also can inhibit
mitoch.complex I causing lactic acidosis (rare).
• Insulin required for cells (e.g.liver,muscle,fat) to take up
glucose and synthesise glycogen.
36
5. MITOCHONDRIAL DISEASES
(e.g. DEFECTIVE ELECTRON
TRANSPORT) AND TREATMENT
A) Creatine therapy
B) Coenzyme Q10 therapy
37
Mitochondrial Myopathies
• Genetic defects in mitochondrial structure &
function leading to defective aerobic energy
transduction and resulting in: exercise intolerance,
lactic acidosis, stroke/seizure, headaches.
38
a) CREATINE THERAPY
Creatine supplementation (an ergogenic aid effective against
mitochondrial myopathies?)
ATP
ADP
k i d n e y
g u a n i d o a c e t a ta er g i n i n e
l i v e r
Pi, 2OH
S AM
• daily requirement is 2g
• daily
C r e dietary
a t i n eintake is 1g (meat,
c r e a tfish,
i n eanimal
p h o sproducts)
p h a t e
c r e a t i n i n
( p h o s p h o c r e a t i n e )
( u r i n e )
• also formed in liver, kidneys,
pancreas
from
the
amino
acids
glycine,
E NE RGY S T ORE
a
n
a
e
r
o
b
i
c
e
x
e
arginine and methionine ir nc i rs ee s t> i n3 g0 ms e uc s c l e
• 5-7g x 4 per day for 5-7 days increases muscle creatine stores by 18%
(particularly in vegetarians); enhances performance in certain
repetitive, high intensity, short-term exercise tasks in healthy
individuals, offsets fatigue in mitochondrial myopathy patients and
improves the mobility of the elderly. J. Amer. Coll. Nutr. 17, 216-234 (1998).
39
b) Ubiquinone (Coenzyme Q10) as a Food Supplement or Therapy
• An essential electron and proton carrier in the mitochondrial respiratory chain.
• Found in all intracellular membranes (acts as a mobile lipid soluble antioxidant
that prevents membrane lipid peroxidation)
• Better antioxidant if reduced to ubiquinol (UQH2) by NADH dehydrogenase
of the respiratory chain.
• Synthesised in mitochondria
• Contributes to the fluidity of the phospholipid bilayer in membranes
• Prevents plasma lipoprotein oxidation
• Is a dietary supplement that protects liver from hepatotoxins (e.g. ethanol)
and partly prevents mitochondrial myopathies (J. Neurol. Neurosurg. Psych. 50,
1475-81)
• Deficiency may occur in patients taking cholesterol lowering drugs (the
statins) which act by inhibiting HMG-CoA reductase (e.g. lovastatin) Proc. Nat.
Acad. Sci. 87, 8931 (1990)
40
6. b-OXIDATION OF FATTY
ACIDS AS AN ENERGY
SOURCE
a) Starvation/diabetes/endstage renal disease
b) Carnitine therapy
c) Ketogenic diet therapy
d) Drug induced non alcoholic steatohepatitis , NASH
e) Alcohol induced steatohepatitis , ASH
41
Stages in the
extraction of
energy from
food stuffs.
42
b-Oxidation of fatty acids - transport of acyl carnitine into the
mitochondrial matrix
Stryer Fig 24-4
43
Fatty acid Metabolism
• Fatty acids are linked to coenzyme A (CoA) before they are oxidised
• Carnitine carries long-chain activated fatty acids into the mitochondrial
matrix
Carnitine therapy for mitochondrial diseases
44
The b-oxidation pathway as an energy source
O
O
R C C C C S CoA
H2 H2 H2
Acyl Co A
oxida tion
R C C C C S CoA
H2 H H
trans -  -En oyl C oA
FAD FADH 2
H 2O
O H O
R C C C C S CoA
H2
H
b-Ketoacyl CoA
H+ + NAD H NAD+
oxida tion
Hyd ration
OHH O
R C C C C S CoA
H2 H H
3-L-hyd ro xyacy l CoA
CoA-SH
Th io lys is
O
R
+
C C S CoA
H2
Acyl
Co A s hortened
by 2 carbon ato ms
O
H3C
C
S CoA
Acetyl Co A
Citric acid cycle
45
a) Starvation/Diabetes/Endstage renal disease
Fat breaks down to acetyl CoA which form
ketone bodies
• Under low carbohydrate condition,
oxaloacetate is converted to
glucose (gluconeogenesis).
2
D -b- H y d r o x y b u t y r
CH3
HC
OH
CH2
COO
NAD+
H+ + N A D H
Ac e t y l
Co A
CoA
O
O
Ac e t y l
+
Co A
C S CoA
H2O CoA
C S CoA
CH3
CH2
CH2
C O
Ac e t y l
Co A
HO CH
C O
Ac e t o a c
H M G C oCH
A2
HM G- Co A
t h i o l a s e
l y a s e
CH3
s y n t h a s e CH2
COO
COO
Ac e t o a c e t y l
b- H y d r o x y - H+
Co A
b- m e t h y l g l u t a r y l
Co A
s u c c i n a t e
c i t r i c
c y c l e
CO2
a c i d
Co A
t r a n s f e r a s e
CH3
C
KETOGENESIS
s u c c i n y l
Ac e t o a c e t a t e
( M E T ABOLI S M
i . e . ,
a c t
a s
Co A
O
CH3
Ac e t o n e
b- h y d r o x y b u t y r a t e
o f
k e t o n e
b o d i e s )
f u e l
a n d s p a r e s
g l u c o s e
46
Diabetic ketoacidosis weakness, dehydration, thirst, drowsiness,coma
• Usually precipitated by infection
• lipolysis is the major energy source increases acetyl CoA levels which
increases ketone body formation.Acetone excreted by the lungs/kidney.
e.g. by starvation or diabetes mellitus (insulin-stimulated glucose entry
into cells is impaired fatty acids are oxidised to maintain ATP levels.
• if citric acid cycle is slowed by thiamine deficiency.
• disease state plasma ketone levels: 10-25 mM (normal <0.5mM) and
acetone breath smell( rotten apples or pear-drop smell)
• LIFE THREATENING: ketogenesis faster than ketone body metabolism
b-hydroxybutyric acid ↑↑> acetoacetic acid ↑& causes severe ACIDOSIS.
Antidote – insulin , water, base therapy (bicarbonate?), carnitine
•  urinary excretion of Na+, K+, Pi, H2O, H+
 dehydration,  blood volume
47
b) Carnitine Therapy
Carnitine alleviates acetyl-CoA mediated inhibition of pyruvate
dehydrogenase.
• Both glycolysis and fatty acid metabolism produce acetyl CoA
• Accumulation of acetyl CoA can inhibit pyruvate dehydrogenase, the
enzyme responsible for producing acetyl CoA from pyruvate.
• Pyruvate will then be converted to lactic acid
• Carnitine can temporarily scavenge acetyl CoA to form acetylcarnitine
thus alleviating lactic acidosis in the muscle.
C
H
3
H
O
C CCC
H
H
2
2
O
C
H
3 O
H
+
H
N
3C
G
L
C
F
O
p
d
A
A
A
X
y
e48
T
Carnitine supplement
Uses
1. Improves quality of life and walking performance in patients with
limited walking capacity e.g., from end-stage renal disease and
peripheral arterial disease.
2. Neurodegenerative diseases and recovery from cerebral ischemia.
3. Possible ergogenic aid but can cause an unpleasant body odour
likened to rotting fish.
4. Improves memory of old rats (PNAS 99, 1876-81 (2002))
Biochemistry
1. Increases carnitine content, carries activated fatty acids across
mitochondrial membrane and required for mitochondrial fatty acid
oxidation.
2. Prevents acetyl CoA accumulation which inhibits pyruvate
dehydrogenase.
3. Chelates iron and stabilizes membranes (antioxidant properties)
49
Carnitine supplement (cont)
Sources
Meat and dairy products exported and synthesized by
liver > kidney from lysine + methionine. Highest levels in
skeletal muscle, heart, adrenal gland but can’t synthesise it
so take it up from the plasma.
- total body store = 20-25gms.
Oral Bioavailability 5-15%
But over-the-counter formulations have low carnitine content and
poor dissolution.
- plasma acylcarnitines accumulate
Journal of the American College of Nutrition, 17, 207-215 (1998)
Progress in Cardiovascular Diseases, 40, 265-286 (1997)
50
c) Ketogenic diet therapy (results 10-25% seizure free & 60% better)
for epileptic children resistant to phenytoin or valproate
Energy Source Normal Diet Ketogenic Diet
Protein
27%
10.4% adequate
Carbohydrate
56%
Fat
17%
89.6%
Ketogenic diet consists of an egg nog that tastes like a mild shake
(or frozen like ice cream)
Supplying the body with fuel in the form of fat and proteins but not
carbohydrates.
fasting, diabeties
Ketogenic diet
Ketone Bodies
Brain uses either
glucose or ketone
bodies as fuel
Liver produces ketone
bodies
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d) Drugs that inhibit fatty acid oxidation cause fatty
liver (steatosis) and 10% get NASH (nonalcoholic
steatohepatitis & liver cancer)
Steatosis (fatty liver) in 33% population & 80% of obese patients. Higher
also in diabetes , high plasma triglycerides. NASH in 2-9% patients
undergoing routine liver biopsy. Hepatocellular carcinoma.
Drugs that inhibit mitochondrial β-fatty acid oxidation
1)Tetracycline, valproic acid,oestrogens,glucocorticoids
2) Amiodarone,perhexiline are charged lipophilic drugs concentrate in
liver mitochondria & inhib. β-fatty acid oxidn & respiration, cause
lipid peroxidn. & reactive oxygen species (ROS). Steatosis and
steatohepatitis are independent. Fibrosis occurs.
3) Drugs induce sporadic events of both e.g. carbamazepine
4) Latent NASH e.g. tamoxifen
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e) Ethanol induced steatohepatitis (ASH)
proposed endotoxin mechanism
1) Ethanol causes lipogenesis and
fatty liver (caused by inhibition of LDL synth. & export).
2) Ethanol oxidised by CYP2E1 to form hydroxyethyl radicals
AND ethanol oxidised by ADH to form acetaldehyde which
cause oxidative stress and hepatocyte & gut cytotoxicity.
3) Oxidative stress disrupts intestinal mucosal cell
actin cytoskeleton (prev. by oats supplement).
4) Intestine becomes leaky & endotoxin enters blood
& liver which causes liver inflammation and ASH.
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JPET 329,952-8(2009)
Drugs causing weight gain in some patients
Tricyclic antidepressants imipramine,amitriptyline,nortryptyline,
Antipsychotics
haloperidol,clozapine,olanzapine,risperidone,chlorpromazine,paxil
Corticosteroids prednisone. Also steroids estrogen,tamoxifen
Antidiabetics rosiglitazone,pioglitazone,insulin
Antirheumatism etanercept,enbrel
Anti-seizure valproate,depakote,carbamazepine
Lithium
MAO inhibitors phenelzine,tranylcypromine (not a hydrazine)
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THE END
• Don’t memorize the following
slides 12,13,14,15,16,19,21
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