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3 Lipid Metabolism
3 Lipid Metabolism
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
Lymphati
exocytosi c vessel
s
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)
triacylglycer
ol
cholesteryl
Apo esters
B Apo E
phospholipids
cholester
ol
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
LIPID
METABOLISM:
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)