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•Fat breakdown
about 50 % of energy in liver, kidney and
skeletal muscles up to 95 % of energy cardiac
muscle
•Fats are the major source of energy for:
fasting animal organism in diabetes
• Fatty acids and glycerol -
substances that are directly used
as a fuel by mammalian organisms.
• Fatty acids (FA) and glycerol for
metabolic fuels are obtained
from triacylglycerols:
(1) In the diet
(2) Stored in adipocytes (fat
storage cells)
• Free fatty acids occur only in
trace amounts in cells
triacylglycerols
phospholipids
Digestion – in small intestine.
cholesterol
Enzyme – pancreatic lipase.
Lipase catalyzes hydrolysis at the C1 and C3 positions of
TGs producing free fatty acids and 2-monoacylglycerol.
Colipase – protein which is present in the intestine and helps
bind the water-soluble lipase to the lipid substrates.
Colipase also activates lipase.
Bile salts (salts of bile acids) are required for lipids digestion.
Bile salts are synthesized in the
liver from cholesterol.
Taurocholate and glycocholate - the most abundant bile salts.
Amphipathic: hydrophilic (blue) and hydrophobic (black)
TGs are water insoluble and lipase is water soluble.
Digestion of TGs takes place at lipid-water interfaces.
Rate of digestion depends on the surface area of the
interface.
Bile salts are amphipathic, they act as detergent
emulsifying the lipid drops and increasing the surface area
of the interface.
Bile salts also activates the lipase.
Inadequate production of bile salts results in
steatorrhea.
Dietary phospholipids are degraded by
phospholipases
Phospholipases are synthesized in the pancreas.
Major phospholipase is phospholipase A2 (catalyses the
hydrolysis of ester bond at C2 of glycerophospholipids
and lysophosphoglycerides are formed).
Lysophospho-
glycerides are
absorbed and in
the intestinal
cells are
reesterified
back to glycero-
phospholipids.
Lysophosphoglycerides can act as detergent
and therefore in high concentration can
disrupt cellular membranes.
CH2 OH CH2 O C R1
O O
CH O C R2 + R1 CO SCoA CH O C R2 + HSCoA
1.
CH2 OH CH2 OH
O O
CH2 O C R1 CH2 O C R1
O O
2.
CH O C R2 + R3 CO SCoA CH O C R2 + HSCoA
O
CH2 OH CH2 O C R3
Lymphatic
exocytosis vessel
VLDL
• are formed in the liver
• contain 50 % of TGs and 22 % of cholesterol
• two lipoproteins — apo B-100 and apo E
• the main transport form of TGs synthesized in the organism (liver)
• deliver the TGs from liver to peripheral tissue (muscle for energy,
adipose for storage)
• bind to membrane-bound lipoprotein lipases (triacylglycerols are again
degraded into free fatty acids and monoacylglycerol)
triacylglycerol
cholesteryl esters
Apo B
Apo E
phospholipids
cholesterol
Lipoproteinlipase – enzyme which is located within
capillaries of muscles and adipose tissue
Function: hydrolyses of TGs of chylomicrons and VLDL.
Formed free fatty acids and glycerol pass into the cells
Chylomicrons and VLDL which gave up TGs are called remnants
of chylomicrons and remnants of VLDL
Remnants are rich in cholesterol esters
Remnants of chylomicrons are captured by liver
Remnants of VLDL are also called intermediate density
lipoproteins (IDL)
Fate of the IDL:
- some are taken by the liver
- others are degraded to the
low density lipoproteins (LDL) (by the removal of more
triacylglycerol)
LDL
LDL are formed in the blood from IDL and in liver from IDL
(enzyme – liver lipase)
xanthomas
HDL
are formed in the liver and partially in small intestine
contain the great amount of proteins (about 40 %)
pick up the
cholesterol from
peripheral tissue,
chylomicrons and
VLDL
enzyme
acyltransferase in
HDL esterifies
cholesterols,
convert it to
cholesterol esters
and transport to
the liver
High serum levels of cholesterol
cause disease and death by
contributing to development of
atherosclerosis
Cholesterol in the
form of HDL is
referred to as "good
cholesterol”
HDL functions as a
shuttle that moves
cholesterol
throughout the body
LDL/HDL Ratio
For a
healthy
person,
the
LDL/HDL
ratio is
3.5
Transport Forms of Lipids
LIPID METABOLISM:
MOBILIZATION OF
TRIACYLGLYCEROLS;
OXIDATION OF
GLYCEROL
Storage and Mobilization of
Fatty Acids (FA)
• TGs are delivered to adipose
tissue in the form of
chylomicrones and VLDL,
hydrolyzed by lipoprotein
lipase into fatty acids and
glycerol, which are taken up
by adipocytes.
• Then fatty acids are
reesterified to TGs.
• TGs are stored in adipocytes.
• To supply energy demands
fatty acids and glycerol are
released – mobilisation of adipocyte
TGs.
At low carbohydrate and insulin concentrations (during
fasting), TG hydrolysis is stimulated by epinephrine,
norepinephrine, glucagon, and adrenocorticotropic
hormone.
TG
hydro-
lysis is
inhibited
by insulin
in fed
state
•Lipolysis - hydrolysis of
triacylglycerols by lipases.
•A hormone-sensitive lipase
converts TGs to free fatty
acids and monoacylglycerol
•Monoacylglycerol is
hydrolyzed to fatty acid
and glycerol or by a
hormone-sensitive lipase or
by more specific and more
active monoacylglycerol
lipase
Transport of Fatty Acids and Glycerol
• Fatty acids and glycerol diffuse
through the adipocyte membrane and
enter bloodstream.
• Glycerol is transported via the blood
in free state and oxidized or converted
to glucose in liver.
• Fatty acids are traveled bound to
albumin.
• In heart, skeletal muscles and liver
they are oxidized with energy release.
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
FATTY ACID
OXIDATION
Stages of fatty acid oxidation
(1) Activation of fatty acids takes place
on the outer mitochondrial membrane
1. Oxidation of acyl
CoA by an acyl CoA
dehydrogenase to
give an enoyl CoA
Coenzyme - FAD
2. Hydration of the
double bond between
C-2 and C-3 by enoyl
CoA hydratase with
the 3-hydroxyacyl
CoA (-hydroxyacyl
CoA) formation
3. Oxidation of
3-hydroxyacyl CoA to
3-ketoacyl CoA by
3-hydroxyacyl CoA
dehydrogenase
Coenzyme – NAD+
4. Cleavage of
3-ketoacyl CoA by
the thiol group of
a second molecule
of CoA with the
formation of
acetyl CoA and an
acyl CoA
shortened by two
carbon atoms.
Enzyme -
-ketothiolase.
The shortened acyl
CoA then
undergoes another
cycle of oxidation
The number of
cycles: n/2-1,
where n – the
number of carbon
atoms
-Oxidation of
Fatty acyl CoA
saturated fatty
acids
• One round of oxidation: 4 enzyme steps
produce acetyl CoA from fatty acyl CoA
• Each round generates one molecule each of:
FADH2
NADH
Acetyl CoA
Fatty acyl CoA (2 carbons shorter each round)
SYNTHESIS OF
FATTY ACIDS
Fatty Acid Synthesis
• Occurs mainly in liver and adipocytes, in
mammary glands during lactation
• Occurs in cytoplasm
• FA synthesis and degradation occur by
two completely separate pathways
• When glucose is plentiful, large amounts
of acetyl CoA are produced by glycolysis
and can be used for fatty acid synthesis
Three stages of fatty acid
synthesis:
A. Transport of acetyl CoA into
cytosol
B. Carboxylation of acetyl CoA
C. Assembly of fatty acid chain
A. Transport of Acetyl CoA to
the Cytosol
• Acetyl CoA from catabolism of
carbohydrates and amino acids is
exported from mitochondria via the
citrate transport system
• Cytosolic NADH also converted to NADPH
• Two molecules of ATP are expended for
each round of this cyclic pathway
Citrate transport
system
Sources of NADPH for Fatty Acid Synthesis
1. One molecule of NADPH is generated for each
molecule of acetyl CoA that is transferred from
mitochondria to the cytosol (malic enzyme).
Enzyme -
acyl-malonyl ACP
condensing enzyme.
Reduction.
Acetoacetyl ACP is
reduced to D-3-
hydroxybutyryl ACP.
NADPH is the
reducing agent
Enzyme: -ketoacyl
ACP reductase
Dehydration.
D-3-hydroxybutyryl
ACP is dehydrated
to form crotonyl
ACP
(trans-2-enoyl
ACP).
Enzyme:
3-hydroxyacyl
ACP dehydratase
Reduction.
NADPH is reductant.
Reduction, dehydration,
and a second reduction
convert the C6--
ketoacyl ACP into a C6-
acyl ACP, which is ready
for a third round of
elongation.
Final reaction of FA synthesis
• Rounds of synthesis continue until a
C16 palmitoyl group is formed
• Palmitoyl-ACP is hydrolyzed by a thioesterase
Protein kinase is
activated by AMP and
inhibited by ATP.
Carboxylase is
inactivated when the
energy charge is low.
Local Regulation
Acetyl CoA carboxylase is allosterically stimulated by
citrate.
The level of citrate is high when both acetyl CoA and ATP
are abundant (isocitrate dehydrogenase is inhibited by
ATP).
Palmitoyl CoA inhibits carboxylase.
Response to Diet
Fed state:
• Insulin level is increased
• Inhibits hydrolysis of stored TGs
• Stimulates formation of malonyl CoA, which inhibits
carnitine acyltransferase I
• FA remain in cytosol (FA oxidation enzymes are in the
mitochondria)
Starvation:
• Epinephrine and glucagon are produced and stimulate
adipose cell lipase and the level of free fatty acids rises
• Inactivate carboxylase, so decrease formation of malonyl
CoA (lead to increased transport of FA into mitochondria
and activate the b-oxidation pathway)
LIPID METABOLISM:
BIOSYNTHESIS OF TRIACYLGLYCEROLS
AND PHOSPHOLIPIDS
Synthesis of Triacylglycerols (TGs)
and Glycerophospholipids (GPLs)
Glycerol 3-phosphate can be obtained either by the
reduction of dihydroxyecetone phosphate (primarily) or
by the phosphorylation of glycerol (to a lesser extent).
Formation of phosphatidate
Two separate acyl transferases (AT) catalyze the
acylation of glycerol 3-phosphate.
The first AT (esterification at C1) has preference for
saturated fatty acids;
the second AT (esterification at C2) prefers
unsaturated fatty acids.
• Phosphatidic acid (phosphatidate) is an
common intermediate in the synthesis of
TGs and GPLs
Phospha-
Triacyl- tidyl-
glycerol
etha-
nolamine
Phosphatidylcholine
Synthesis of TGs
Diacylglycerol can
be acylated to
triacylglycerol (in
adipose tissue
and liver)
Enzyme:
acyltransferase
Synthesis of neutral phospholipids
CDP-choline or CDP-ethanolamine are formed from
CTP by the reaction: