Lipid Metabolism
Digestion and Absorption of Dietary Lipids
• Lipids are taken in the diet mainly as
triacylglycerol
•.
In addition, small amounts of
phospholipids, cholesterol, carotenoids
and fat-soluble vitamins are taken in diet.
I- Digestion of Triacylglycerol
• 1- Lingual lipase
• 2- Gastric lipase
• 3- Pancreatic lipase, is the main digestive lipase.
Emulsification of lipids is important for the action
of pancreatic lipase. Emulsification involves mixing
in the duodenum with bile salts, phospholipids and
lysophospholipids in addition to monoacylglycerol.
This leads to breaking of lipid droplets into smallersized structures, which increases their surface area
exposed to enzyme.
I- Digestion of Triacylglycerol
• The products of digestion by pancreatic lipase
are:
• 72% as 2-monoacylglycerol (MAG)
• 22% as glycerol and free fatty acids
• 6% as 1-monacylglycerol
• 4- Intestinal lipase: This intracellular enzyme
hydrolyzes 1-monoacylglycerol to glycerol and
free fatty acid.
II- Digestion of Phospholipids
III-Cholesterol esters
• II- Digestion of Phospholipids
• Phospholipids may be absorbed without
digestion. Also they may be hydrolyzed by
pancreatic
phospholipase
A2
to
lysophospholipids.
The
resulting
lysophospholipids act as emulsifying agents.
• III- Digestion of cholesteryl ester
• Cholesteryl ester is hydrolyzed by pancreatic
cholesterol
esterase
(cholesteryl
ester
hydrolase) into cholesterol and fatty acid.
Digestion of Dietary Lipids
FA1
H2O
FA1
FA3
FA2
FA2
FA2
FA3
Pancreatic
lipase
Pancreatic
lipase
OH
OH
2- MAG (72%)
1,2- DAG
TAG
OH
FA1
H2O
Isomerase
FA1
H2O
OH
HO
HO
Pancreatic
lipase
OH
Glycerol (22%)
FA1
H2O
FA2
FA1
HO
FA2
Pancreatic
Phospholipase A2
P – Base
P – Base
Lysophospholipids
Phospholipids
H2O
FA1
FFA
Cholesterol
Cholesteryl esters
Cholesterol esterase
OH
1- MAG (6%)
Absorption of Dietary Lipids
• Bile salts together with products of digestion
form micelles. These micelles are soluble thus
allowing the products of digestion, together
with fat-soluble vitamins to be transported to
the brush border of the mucosal cells to be
taken to the inside of the epithelial cells. Bile
salts pass to the ileum, where most are
reabsorbed into the enterohepatic circulation.
Diagram for Digestion and Absorption of Lipids
Intestinal Lumen
Mucosal Cells
TAG
Chylomicrons
Pancreatic
lipase
Lacteals
FFA
Phospholipids
Free cholesterol
Cholesterol-esters
ApoA, B-48
DAG
Pancreatic
lipase
FFA
FFA
2-MAG
TAG
2-MAG
Thiokinase
Acyl- CoA
CoA , ATP
Isomerase
Glycerol
kinase
FFA
1-MAG
1-MAG
ATP
Intestinal
lipase
Pancreatic
lipase
Glycerol 3-P
Glycerol
Glycolysis
FFA
Glycerol
Glucose
DHAP
Glycerol
Portal blood
Chylomicron Structure
A
Apo A
Free cholesterol
Cholesteryl-ester
Phospholipids
B-48
TAG
Apo B-48
The formed triacylglycerol with cholesteryl ester
(hydrophobic core) are surrounded by a single layer of
phospholipid and cholesterol together with proteins (apo A
and apo B-48) to form minute particles < 1μm called
chylomicrons within the mucosal cells which are
transported to the lymphatics (lacteals).
Fate of Absorbed Lipids
• I- Uptake by tissues
• About 90% of triacylglycerol in the chylomicrons are
hydrolyzed by the enzyme lipoprotein lipase This enzyme is
present in the endothelial cells of extrahepatic tissue
(muscle and adipose tissue). Its synthesis is increased by
insulin.
• Heparin stimulates the release of lipoprotein lipase thus
clearing plasma turbidity due to the absorbed
chylomicrons, thus heparin is called a clearing factor.
• Hydrolysis of the triacylglycerol yields free fatty acids
(FFAs) and glycerol. Most of the FFAs are taken by the
extrahepatic tissue.
• The released glycerol is taken by the liver and the kidney
where it can be utilized by the glycerol kinase in these
tissues.
Fate of Absorbed Lipids
• II-Utilization by tissues
• 1- Oxidation: Fatty acids are mostly oxidized by β-oxidation. Glycerol
is oxidized by joining the glycolysis pathway.
• 2- Conversion to glucose: glycerol (10% of fats) can be converted to
glucose. The last 3 carbons of odd chain fatty acids (which are rare in
natural fat) may also be converted to glucose.
• 3- Formation of tissue fat.
• III-Storage
• This occurs mainly in the adipose tissue as triacylglycerol (DEPOT
FAT).
• IV-Excretion
• Fats may be secreted in sebaceous glands and also by mammary
gland in milk.
Compare between:
• Tissue fat:
• Depot fat:
• Constant element (not
• Variable element
affected by diet)
(affected by diet)
• Consists mainly of :
Phospholipids, glycolipids.
• Consists mainly of TAG
• Site:
cell
membrane,
mitochondrial membrane
and nervous tissue.
•
•
•
•
•
Functions:
1- membrane permeability
2- ETC
3- Nerve impulse transmission
4- tissue support and
protection
• Site: Adipose tissue
• Function: Source of
energy
Oxidation of Fatty Acids
• Free fatty acids are taken by most of the
tissues. Oxidation of the fatty acids is
principally by β- oxidation in the
mitochondrial matrix (adjacent to the
TCA cycle and the respiratory chain).
• In the mitochondria, fatty acids are
oxidized to acetyl-CoA. Acetyl-CoA may
be further oxidized completely in the TCA
cycle.
Activation of the fatty acid
• is catalyzed by acyl-CoA synthetase (key enzyme). This
step requires ATP and so it is irreversible
Acyl- CoA synthetase
R – CO ~ S – CoA
R – COOH
FFA
Acyl- CoA
CoA-SH
ATP
PPi + AMP
2Pi
Transport of acylCoA into the mitochondria
• Long chain fatty acyl-CoA : They are transported to
the mitochondrial matrix by carnitine shuttle
Transport of Acyl-CoA into Mitochondria (Carnitine Shuttle)
FFA
Cytosol
Outer
membrane
CoA-SH
Acyl-CoA
CoA-SH
ATP
Carnitine-palmitoyl
transferase I
Acyl-CoA
synthetase
Inter-membrane
space
Carnitine
Acyl-carnitine
Carnitine Acyl-carnitine
translocase
Inner
membrane
Carnitine-palmitoyl
transferase II
Mitochondrial matrix
Carnitine
Acyl-CoA
CoA-SH
Acyl-carnitine
-oxidation of Acyl-CoA
O
R – CH2
CH2 – C ~ S – Co A
Acyl-CoA ( Cn )
Acyl- CoA
dehydrogenase
ETC
2 ADP + 2 Pi
[O] +
FADH2
O
R – CH
2 ATP
H2O +
FAD
CH – C ~ S – Co A
2– Trans- enoyl-CoA
Repeat
The
Cycle
H2O
2– Trans-enoyl-CoA hydratase
OH
R – CH
O
CH2 – C ~ S – Co A
L,3- Hydroxyacyl-CoA
H2O +
NAD+
L,3- Hydroxyacyl-CoA
dehydrogenase
NADH,H+
O
3 ATP
ETC
[O] +
3 ADP + 3 Pi
O
R – C ~ CH2 – C ~ S – Co A
3- Ketoacyl-CoA
CoA-SH
-Ketothiolase
O
O
R– C ~ S – CoA
Acyl- CoA (Cn-2 )
CH3– C ~ S – CoA
Acetyl- CoA
Citric Acid Cycle
& ETC
2CO2 + 12 ATP
Energy yield
• Energy yield: Oxidation of palmitic acid (C16) results in the
formation of 8 molecules of acetyl-CoA through passing
through 7 cycles.
• Each cycle yields one molecule of NADH and one
molecule of FADH2.These reduced coenzymes will yield 5
ATPs via the respiratory chain. So in 7 cycles: 7 X5 =35
ATPs are produced. The 8 molecules of acetyl CoA will
produce 8 X 12=96 ATPs by oxidation in Krebs’ cycle and
ETC.
• Thus a total of 35 + 96 = 131 ATPs are produced from
complete oxidation of one molecule of palmitic acid.
Since 2 high energy phosphates are used in the activation
of the fatty acid, so the net gain is 131-2= 129 ATPs
•
ATP Produced by Oxidation of Palmitic Acid
CH3(CH2)14-CO ~ S –CoA Palmitoyl-CoA
7 Cycles of β-oxidation
7 FADH2 + 7 NADH,H+ + 8 Active acetate
ETC
TCA cycle
& ETC
ETC
16 CO2
14 ATP
+ 21 ATP
+ 96 ATP =
131
- 2 for activation = 129 ATP
N.B : Oxidation of odd chain fatty acids leaves the
last 3 carbons as propionyl-CoA. Propionyl-CoA is
carboxylated to methylmalonyl-CoA which is
isomerized to succinyl-CoA which enters Krebs’ cycle.
• Regulation of β-Oxidation
• It depends upon the availability of fatty acids and the
consumption of ATP.
• 1-Availability of fatty acids: Carbohydrate feeding leads to
release of insulin. Insulin stimulates lipogenesis and inhibits
lipolysis thus decreasing FFA.
• Also during carbohydrate feeding, synthesis of fatty acids is
stimulated and so, excess malonyl-CoA is formed. MalonylCoA inhibits CPT-I thus inhibiting the uptake and oxidation
of the fatty acids. Thus the 2 processes, synthesis and
oxidation do not go together.
• 2- β-oxidation in a cell depends upon its consumption of
ATP. High ATP (and low ADP& Pi) inhibits the respiratory
chain, thus β- oxidation becomes inhibited.
Regulation of Fatty Acid β-Oxidation
Fatty acids
ATP/ADP
_
Fatty acyl-CoA
Electron transport
chain
CPT I
_
Fatty acyl-carnitine
NADH & FADH2
_
β-Oxidation
Acetyl-CoA
Malonyl-CoA
Acetyl-CoA
Carboxylase
+
Insulin
Acetyl-CoA
Compound Lipids
Phospholipids
Glycerophospholipids
- Phosphatidic acid
- Phosphatidylcholine (lecithin)
- Phsphatudylethanolamine
-Phosphatidylinositol
Sphingolipids
Sphingophospholipids
- Sphingomyelin
Glycolipids
- Cerebrosides
- Sulfatides
- Globosides
- Gangliosides
Metabolism of Ketone Bodies
• Ketogenesis
• Ketone bodies are acetoacetate, βhydroxybutyrate and acetone. Synthesis of
ketone bodies occurs in the mitochondria of
the liver. This is because of the presence of
HMG-CoA synthase and HMG-CoA lyase
chiefly in the liver. The building unit of ketone
bodies is acetyl-CoA derived mainly from
oxidation of fatty acids.
Diagram for Ketogenesis
CH3- CO ~ S – CoA
Acetyl-CoA
Acyl- CoA
-Oxidation
-Oxidation
Last C4
Ketogenic
Amino acids
Ketothiolase
CoA-SH
Acetoacetyl-CoA
HMG-CoA Synthase
H2O
(Liver mitochondria)
Acetyl-CoA
CoA-SH
3-Hydroxy-3-methyl glutaryl-CoA (HMG-CoA)
HMG-CoA Lyase
(Liver mitochondria)
CH3- CO ~ S – CoA
Acetyl-CoA
Acetoacetate
Spontaneous
(Lungs & Kidneys)
CO2
Acetone
(Expired air & Urine)
NADH,H+
3- hydroxybutyrate
Dehydrogenase
NAD+
3- Hydroxybutyrate
• Importance of Ketogenesis
• Ketogenesis is of great importance during
starvation when fats represents the main source
of energy. Although most tissues can utilize fatty
acids, they can utilize ketone bodies more easily.
During prolonged fasting, the brain adapt to
utilize ketone bodies as it cannot utilize fatty
acids (fatty acids are bound to plasma albumin
and cannot pass the blood brain barrier). Thus
ketogenesis is a preparatory step by the liver to
facilitate the oxidation of fatty acids during
starvation and to provide energy for
extrahepatic tissues including the brain.
Ketolysis
• It is the complete oxidation of ketone bodies in the
mitochondria of extrahepatic tissue. This is due to the high
activity of thiophorase (succinyl-CoA:acetoacetate CoA
transferase) in the extrahepatic tissue and its deficiency in
the liver. β–hydroxybutyrate is converted to acetoacetate,
which gives two molecules of acetyl-CoA. Acetyl-CoA is
utilized by Krebs’ cycle for complete oxidation.
• Ketolysis is dependent on activity of citric acid cycle as
succinyl-CoA needed for the thiophorase reaction is
supplied from citric acid cycle and acetyl-CoA enters the
cycle for complete oxidation.
Diagram for Ketolysis
CH3-CHOH-CH2-COOH
3- hydroxybutyrate
NAD+
3- hydroxybutyrate
Dehydrogenase
NADH,H+
Succinyl-CoA
CH3-CO~CH2-COOH
Acetoacetate
CoA Transferase
Mitochondria of extrahepatic
tissues
Citric acid cycle
Acetoacetyl-CoA
CH3-CO~CH2-CO ~ S - CoA
Citrate
Succinate
Ketothiolase
CoA-SH
Oxaloacetate
2 CH3-CO ~ S - CoA
Acetyl-CoA
Ketosis
• This is a condition characterized by increased
ketone bodies in the blood (ketonemia) and in
the urine (ketonuria).
• Normally ketone bodies in blood ranges from
0.5-3mg/dL. In urine, it is less than 15mg/day.
•
Causes of Ketosis
• Ketosis occurs in conditions where the rate of
ketogenesis exceeds the rate of ketolysis i.e. in
conditions where there is marked stimulation of
ketogenesis, as in the following:
• -Starvation, low carbohydrates and high fat in
diet
• -Severe diabetes mellitus
• -Prolonged
administration
of anti-insulin
hormones
• -Prolonged and severe muscular exercise
•
Effects of ketosis
• The increased production and loss of βhydroxybutyrate and acetoacetate leads to
excessive loss of buffer cations Na+, K+ and NH4+ in
urine associated with decreased bicarbonate in the
blood, which causes acidosis and may lead to coma
and death.
• Ketogenic substances include fatty acids, ketogenic
amino acids and anti-insulin hormones
• Anti-ketogenic substances include carbohydrates,
glucogenic amino acids, glycerol and insulin.
•
Diagram for Metabolic Changes
Adipose Tissue
During Ketosis
TAG
Increased of Antiinsulin / Insulin
ratio in Blood
Activation of
Lipolysis
Brain
Oxidation for energy
production
Glycerol
FFA
Glucose
Glucose
Glucose
BLOOD
Glycerol
Ketone bodies
Oxidation for energy
production
FFA
Gluconeogenesis
Ketogenesis
- Pyruvate
- Lactate
Ketone bodies
- Oxaloacetate
- Glucogenic
amino acids
Liver
Ketogenic
Amino acids
Acetyl-CoA
ketolysis
Ketone bodies
In Urine
(ketonuria)
Ketone bodies
Extrahepatic Tissues
(muscles)
Metabolism of Cholesterol
• Biosynthesis of Cholesterol
• It is synthesized in the cytosol and endoplasmic
reticulum in all nucleated cells. Plasma cholesterol is
made in the liver and intestine. Acetyl-CoA is the source
of all cholesterol carbons.
• Cholesterol synthesis starts by the formation of HMGCoA in the same way as in ketogenesis except that it is
in the cytosol (ketogenesis occurs in mitochondria).
• HMG-CoA is reduced to mevalonate in a reaction
catalyzed by HMG-CoA reductase (Key enzyme) and
requiring two NADPH.
Importance of Cholesterol
• 1-Formation of lipoproteins: Cholesterol
regulates membrane fluidity.
• 2-Synthesis of vitamin D3: Cholesterol is
dehydrogenated,
forming
7dehydrocholesterol. The latter is converted
into vitamin D3 under the skin by ultra-violet
rays.
• 3-Formation of steroid hormones: Cholesterol
is the precursor of all steroid hormones,
androgens, estrogens, progesterone, and
corticoids.
Importance of Cholesterol
• 4-Formation of bile acids and salts: Primary bile
acids, are synthesized from cholesterol in the
liver. Subsequently; these acids are conjugated
with glycine or taurine to form (bile salts)
• Bile salts are important for emulsification of fats,
thus important for digestion and absorption of
fats.
• Intestinal
bacteria
deconjugate
and
dehydroxylate the primary bile acids converting
them into secondary bile acid.
• Excretion of Cholesterol
• About 50% of cholesterol is excreted in feces
as bile acids; the remaining 50% are excreted
also in stools as neutral sterol (coprostanol).
• Plasma Cholesterol
• The total plasma cholesterol level ranges from
120-240 mg/dL (recommended level is less
than 200 mg/dL). About two thirds are
present as cholesteryl ester and one third is
present as free cholesterol.
Hypercholesterolemia
• Hypercholesterolemia means a plasma cholesterol
level higher than 240 mg/dL. There are some factors
which may lead to it, these include:
• 1-Dietary causes: Diet rich in saturated fat,
carbohydrates and cholesterol.
• 2- Obesity
• 3-Diabetes mellitus
• 4-Hypothyroidism: as thyroid hormone stimulates the
oxidation of cholesterol and its conversion to bile acids.
• 5-Obstructive jaundice: This blocks the pathway for
excretion of cholesterol and bile acids.
• 6-Nephrosis:
• 7-Familial hyperliopoproteinemias
Plasma Lipids and Lipoproteins
• Lipids are transported as lipoproteins with
special arrangement, so that the most
hydrophobic one is present in the core
(triacylglycerol and cholesterol-esters).These
are surrounded by the amphipathic lipids
(phospholipids
and
cholesterol)
and
apolipoproteins.
•
Types of plasma lipoproteins:
• 1- Chylomicrons: Synthesized in intestinal cells and consist
mainly of TAG.
• 2- Very Low Density Lipoprotein (VLDL): synthesized in
liver and consist mainly of TAG.
• 3- Low Density Lipoprotein (LDL): synthesized in liver and
consist mainly of cholesterol. LDLs are important source of
cholesterol to extrahepatic tissues. High levels of LDLcholesterol increase the risk of atherosclerosis.
• 4- High Density Lipoprotein (HDL):
synthesized in
extrahepatic tissues and consist mainly of phospholipids
HDLs are important for removal of cholesterol from the
tissues to the liver (reverse cholesterol transport) and high
levels of HDL protect against atherosclerosis.