Transcript Lipogenesis (2014)

Lipogenesis
Fats not only obtained from the diet but also obtained from lipogenesis in
the body. Lipogenesis means synthesis of fats from CHO and proteins
present in excess of body need.
Lipogenesis requires:
1- Synthesis of fatty acids (FA) and glycerol
2- Activation of fatty acids by CoA and glycerol by glycerokinase,
3- Combination of activated fatty acid and glycerol to give TAG (fats).
De no vo synthesis of fatty acid (cytoplasmic synthesis):
Occur mainly for the synthesis of palmitic acid
Site: Cytoplasm of liver, mammary glands and adipose tissues.
Steps:
1- Transport of acetyl CoA to cytoplasm: Acetyl CoA is the precursor
of fatty acid synthesis. It is produced from oxidation of glucose (by
oxidative decarboxylation of pyruvate) and metabolism of ketogenic
and mixed amino acids.
Acetyl CoA is produced in mitochondria, and FA synthesis occurs in
cytoplasm, so acetyl CoA must be transferred to cytoplasm across
mitochondrial membrane which is impermeable to CoA. The
transport occur through condensation of
acetyl CoA inside
mitochondria with oxaloacetate (OAA) to form citrate which can be
transferred into cytoplasm. In cytoplasm, citrate is cleaved by ATPcitrate lyase or called citrate cleavage system in the presence of
ATP and CoA to give acetyl CoA and OAA.
Transport of acetyl CoA from mitochondria to cytoplasm:
Mitochondria:
OAA + Acetyl CoA
-CoA
↓ citrate synthase
Citrate
Inner mitochondrial membrane
↓
Citrate
+ CoA, ATP
↓ ATP citrate lyase
Cystosol
OAA + Acetyl CoA
2-Conversion of acetyl CoA into malonyl CoA by acetyl CoA
carboxylase
This step is the rate limiting step in FA synthesis and acetyl CoA
carboxylase is the rate limiting enzyme.
3- Remaining series of the pathway is catalyzed by fatty acid
synthase which is a multifunctional enzyme.
Reaction catalyzed by Acetyl CoA Carboxylase
For illustration only
Regulation of acetyl CoA carboxylase:
A) Allosteric regulation: allosterically activated by citrate & ATP and
inhibited by the end product of the pathway (palmitic acid).
B) B) Hormonal regulation: activated by insulin, inhibited by
adrenaline and glucagon (anti-insulin hormone).
C) Dietary regulation: prolonged consumption of high claoric diet (e.g
CHO diet) increases the synthesis of acetyl CoA carboxylase and so
increase FA synthesis. Fat-free diet, fasting and low CHO reduce
enzyme synthesis and so FA synthesis.
Elongation of fatty acids: Mitochondrial synthesis
Palmitic acid - the end product of FA synthesis in cytoplasm
can be elongated in mitochondria by the addition of two carbon
atoms to give other long chain saturated FA e.g. stearic acid
Unsaturation: occur also in mitochondria by desaturase enzyme
to give unsaturated fatty acids e.g. oleic acid
Biosynthesis of TAG from synthesized fatty acid and glycerol:
Site: cytoplasm of liver and adipose tissues
Steps: see figure
1- Activation of fatty acids into acyl CoA
2- Activation of glycerol into 3-glycerophosphate
3-Combination of activated fatty acid and glycerol to form DAG
then TAG as in figure.
A)
CH2-OH
Synthesis of TAG (for illustration)
CH-OH
B)
CH 2-OH
2 RCOOH
Glycerol
Fatty acid
ATP
Lecithicin
glycerokinase
2 CoASH
ADP
TAG
thiokinase
CH2-OH
CH-OH
O
2 RC-SCoA
CH 2-O-PO 3
3-glycerophosphate
- 2CoA
CDP -choline
Acyl CoA, acyl
transferase
CH2O-CO-R1
CH2-O-CO-R1
Phosphatase
CH-O-CO-R2
CH 2-O-PO 3
CH 2O-CH 3O-R 2
pi
CH 2-O-H
1,2 diacylglycerol (DAG)
Phosphatidic acid
Comparison between de novo synthesis and degradation (β-oxidation) of long chain
saturated fatty acids:
Definition
Lioplysis (fatty acid βoxidation
Degradation of depot fat
(release of FFA from
stored TAG, then oxidized
to give energy fat)
Lipogenesis (fatty acid
synthesis)
Synthesis of fat
(triglycerides) from CHO
and protein that exceed the
body need
Greatest flux of pathway
(diet regulation)
Hormonal state that favor pathway
Major tissue site (organ)
Tissue location for fatty acid
synthesis or degradation
Two-carbon donor/product
Allosteric Activator
Allosteric Inhibitor
Carrier of acyl/acetyl groups
between mitochondria and cytosol
H-carrier
NB: the synthesis of TAG occurs mainly in liver and mammary glands but it is stored mainly in
adipose tissue and muscles
Types of body fat
Depot fat (stored fat)
It is a fat stored in the fat cells of adipose tissues. The amount and
composition of depot fat varies according to the nutritional state of the
individuals so it is called variable elements.
Source: The origin of depot fat is dietary fat and lipogenesis.
Composition: Triglycerides mainly
Fate: Source of energy for body by first lipolysis (release of fatty
acids from fats) by hormone sensitive lipase (HSL) which is inhibited
by insulin and activated by adrenaline and glucagon.
Tissue fat (constant element)
Def. It is the fat present in each cell. It is the lipids that enter in the
structure of body cells as cell membrane and mitochondria.
It is not affected by hormones.
It is never used as source of energy i.e. never oxidized to give energy.
Depot fat
Tissue fat
It is the fat stored in fat cells of adipose tissue.
This fat derived from dietary fat and
lipogenesis
Variable element
It is the fat that enter in the structure of
cell membranes
Present in certain tissues as liver and adipose
tissues under the skin, around certain organs
as kidney
Present in every cells
Formed mainly from triglycerides
Formed mainly of cholesterol,
phospholipids and glycolipids
Affected by hormones (How?)
Not affected by hormones
Used in starvation
Not used
Constant element
Functions: source of energy, protection and
Enter in the structure of cell membrane
insulator of heat, fixation of certain organs as Never used as source of energy.
kidney