Dr Ahmed Khamis Salama
Medical Biochemistry
Lipid Metabolism
Fatty Acid Synthesis
The synthesis of malonyl-CoA is the first step of fatty acid
synthesis.
The enzyme that catalyzes this reaction, acetyl-CoA
carboxylase (ACC), is the major site of regulation of fatty
acid synthesis.
Like other enzymes that transfer CO2 to substrates, ACC
requires a biotin co-factor.
The rate of fatty acid synthesis is controlled by the
equilibrium between monomeric acetyl Co-A carboxylase
(ACC) and polymeric ACC. The activity of ACC requires
polymerization. This conformational change is enhanced
by citrate and inhibited by long-chain fatty acids.
The synthesis of fatty acids from acetyl-CoA and malonylCoA is carried out by fatty acid synthase (FAS).
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Dr Ahmed Khamis Salama
Medical Biochemistry
The primary fatty acid synthesized by fatty acid synthase
(FAS) is palmitate CH3 (CH2)14 COO- . Palmitate is then
released from the enzyme and can then undergo separate
elongation
‫ةةةة‬
‫االطالةةةة لةةةةة الكركةةةةر ال‬
and/or
unsaturation to yield other fatty acid molecules.
Origin of Cytoplasmic Acetyl-CoA
Acetyl-CoA is generated in the mitochondria primarily from
two sources:
1. The pyruvate dehydrogenase (PDH) reaction
2. Fatty acid oxidation
In order for these acetyl units to be utilized for fatty acid
synthesis they must be present in the cytoplasm.
Acetyl-CoA enters the cytoplasm in the form of citrate via
the TCA cycle ( see the figure).
In the cytoplasm, citrate is converted to oxaloacetate and
acetyl-CoA by the ATP driven ATP-citrate lyase reaction.
The resultant oxaloacetate is converted to malate by
malate dehydrogenase (MDH).
The malate produced by
this pathway can undergo oxidative decarboxylation by
malic enzyme to give pyruvate.
The co-enzyme for this
reaction is NADP+ generating NADPH.
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Dr Ahmed Khamis Salama
Medical Biochemistry
The advantage of this series of reactions for converting
mitochondrial acetyl-CoA into cytoplasmic acetyl-CoA is
that the NADPH produced by the malic enzyme reaction
can be a major source of reducing co-factor for the fatty
acid synthase activities.
Pathway for the movement of acetyl-CoA units from the mitochondrion to the
cytoplasm for use in lipid and cholesterol biosynthesis.
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Dr Ahmed Khamis Salama
Medical Biochemistry
Synthesis of Triglycerides
Fatty acids are stored for future use as triglycerides in all
cells, but primarily in adipocytes of adipose tissue.
Triglycerides constitute molecules of glycerol to which
three fatty acids have been esterified.
The fatty acids present in triglycerides are predominantly
saturated.
The major building block for the synthesis of triglycerides,
in tissues other than adipose tissue, is glycerol.
Adipocytes
lack
glycerol
kinase,
therefore,
dihydroxyacetone phosphate (DHAP), produced during
glycolysis, is the precursor for triglyceride synthesis in
adipose tissue.
This means that adipoctes must have glucose to oxidize in
order to store fatty acids in the form of triglycerides.
Dihydroxyacetone phosphate (DHAP) can also serve as a
backbone precursor for triglyceride synthesis in tissues
other than adipose, but does so to a much lesser extent
than glycerol.
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Dr Ahmed Khamis Salama
Medical Biochemistry
Triglycerides, as major components of very low density
lipoprotein (VLDL) and chylomicrons, play an important
role in metabolism as energy sources and transporters of
dietary fat.
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Dr Ahmed Khamis Salama
Medical Biochemistry
They contain more than twice as much energy (9 kcal/g)
as carbohydrates and proteins.
In
the
intestine,
triglycerides
are
split
into
monoacylglycerol and free fatty acids in a process called
lipolysis, with the secretion of lipases and bile, which are
subsequently moved to absorptive enterocytes, cells lining
the intestines.
The triglycerides are rebuilt in the enterocytes from their
fragments and packaged together with cholesterol and
proteins to form chylomicrons. These are excreted from
the cells and collected
by the lymph
system
and
transported to the large vessels near the heart before
being mixed into the blood. Various tissues can capture
the chylomicrons, releasing the triglycerides to be used as
a source of energy.
Fat and liver cells can synthesize and store triglycerides.
When the body requires fatty acids as an energy source,
the hormone glucagon signals the breakdown of the
triglycerides by hormone-sensitive lipase to release free
fatty acids. As the brain cannot utilize fatty acids as an
energy source (unless converted to a ketone), the glycerol
component of triglycerides can be converted into glucose,
via gluconeogenesis, for brain fuel when it is broken down.
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Dr Ahmed Khamis Salama
Medical Biochemistry
Fat cells may also be broken down for that reason, if the
brain's needs ever outweigh the body's.
Triglycerides cannot pass through cell membranes freely.
Special enzymes on the walls of blood vessels called
lipoprotein lipases must break down triglycerides into free
fatty acids and glycerol. Fatty acids can then be taken up
by cells via the fatty acid transporter (FAT).
ROLE OF TRIGLYCERIDES IN DISEASE
High level of triglycerides caused Hypertriglyceridemia.
In the human body, high levels of triglycerides in the
bloodstream have been linked to ATHEROSCLEROSIS
(thickening and loss of elasicity of arterial walls) and, by
extension, the risk of heart disease and stroke. Another
disease caused by high triglycerides is PANCREATITIS
‫ياس‬
‫ التهاب البن‬.
Phospholipid Structures
Phospholipids are synthesized by esterification of an
alcohol to the phosphate of phosphatidic acid (1,2diacylglycerol 3-phosphate).
Most phospholipids have a saturated fatty acid on C-1 and
an unsaturated fatty acid on C-2 of the glycerol backbone.
The most commonly added alcohols (serine, ethanolamine
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Dr Ahmed Khamis Salama
Medical Biochemistry
and choline) also contain nitrogen that may be positively
charged, whereas, glycerol and inositol do not.
The major classifications of phospholipids are:
Phosphatidic acid consists of a glycerol backbone, with, in
general, a saturated fatty acid bonded to carbon-1, an
unsaturated
fatty
acid
bonded
to
carbon-2,
and
a
phosphate group bonded to carbon-3.
Phosphatidylcholine (PC)
Phosphatidylethanolamine
(PE)
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Dr Ahmed Khamis Salama
Medical Biochemistry
Phosphatidylserine (PS)
Phosphatidylinositol (PI)
Phosphatidylglycerol (PG)
Diphosphatidylglycerol
(DPG)
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Dr Ahmed Khamis Salama
Medical Biochemistry
CHOLESTEROL METABOLISM
Cholesterol is an extremely important biological molecule
because it :
1. has roles in membrane structure
2. is precursor for steroid hormones synthesis
3. is precursor for the synthesis of bile acids
Both dietary cholesterol and that synthesized de novo are
transported
through
the
circulation
in
lipoprotein
particles. The same is true of cholesteryl esters, the form
in which cholesterol is stored in cells.
The synthesis and utilization of cholesterol must be tightly
regulated in order to prevent over-accumulation and
abnormal deposition within the body.
Of
particular
importance
clinically
is
the
abnormal
deposition of cholesterol and cholesterol-rich lipoproteins
in the CORONARY ARTERIES. Such deposition, eventually
leading to atherosclerosis, is the leading contributory
factor in diseases of the coronary arteries.
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Dr Ahmed Khamis Salama
Medical Biochemistry
Cholesterol
Biosynthesis of Cholesterol
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Dr Ahmed Khamis Salama
Medical Biochemistry
The Utilization of Cholesterol
Cholesterol is transported in the plasma predominantly as
cholesteryl esters associated with lipoproteins.
Dietary cholesterol is transported from the small intestine
to the liver within chylomicrons.
Cholesterol synthesized by the liver, as well as any dietary
cholesterol in the liver that exceeds hepatic needs, is
transported in the serum. Cholesterol is excreted in the
bile as free cholesterol or as bile salts following conversion
to bile acids in the liver.
Bile Acids Synthesis and Utilization
The end products of cholesterol utilization are the bile
acids, synthesized in the liver.
Synthesis of bile acids is one of the predominant
mechanisms for the excretion of excess cholesterol.
However, the excretion of cholesterol in the form of bile
acids is insufficient to compensate for an excess dietary
intake of cholesterol.
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Dr Ahmed Khamis Salama
Medical Biochemistry
Synthesis of the two primary bile acids, cholic acid and
chenodeoxycholic acid.
The
most
abundant
bile
acids
in
human
bile
are
chenodeoxycholic acid (45%) and cholic acid (31%).
These are referred to as the primary bile acids. Within the
intestines the primary bile acids are acted upon by
bacteria and converted to the secondary bile acids,
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Dr Ahmed Khamis Salama
Medical Biochemistry
identified as deoxycholate (from cholate) and lithocholate
(from chenodeoxycholate). Both primary and secondary
bile acids are reabsorbed by the intestines and delivered
back to the liver via the portal circulation.
Clinical Significance of Bile Acid Synthesis
Four physiologically functions for bile acids:
1. Their synthesis and subsequent excretion in the
feces represent the only significant mechanism for
the elimination of excess cholesterol.
2. Bile acids and phospholipids solubilize cholesterol in
the bile, thereby preventing the precipitation of
cholesterol in the gallbladder.
3. They facilitate the digestion of dietary triglycerides
by acting as emulsifying agents that render fats
accessible to pancreatic lipases.
4. They facilitate the intestinal absorption of fatsoluble vitamins.
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