Transcript 第六章 脂类代谢

Chapter 5
Metabolism of Lipids
The biochemistry and molecular
biology department of CMU
Concept
• Lipids are substances that are
insoluble or immiscible in water, but
soluble in organic solvents.
Fats (Triglyceride or
triacylglycerole)
To store and
supply
energy
Lipids
Phospholipids
Glycolipids
Lipoids
Cholesterol
Cholesterol ester
To be
important
membrane
components
Contents
Section 1 Fatty acids
Section 2
Metabolism of Triglycerids
Section 3 Metabolism of Phospholipids
Section 4 Metabolism of Cholesterols
Section 5 Metabolism of Plasma
Lipoproteins
Section 1 Fatty acids
§1.1 Classification of fatty acids
Numerical Symbol
Common Name
Comments
14:0
Myristic acid
Saturated
16:0
Palmitic acid
Saturated
18:0
Stearic acid
Saturated
16:1 Δ 9
Palmitoleic acid
Unsaturated
18:1 Δ 9
Oleic acid
Unsaturated
18:2 Δ 9,12
Linoleic acid
EFA
18:3 Δ 9,12,15
Linolenic acid
EFA
20:4 Δ 5,8,11,14
Arachidonic acid
EFA
Essential Fatty Acids (EFA)
• Linoleic, linolenic and arachidonic
acids are called essential fatty acids,
because they cannot be synthesized
by the body and must be obtained
through diet.
§1.2 Important Derivatives of
Arachidonic acids
Arachidonic acids (AA) in turn gives
rise to biologically important
substances known as the eicosanoids.
• Prostaglandins (PGs)
• Thromboxanes (TXs)
• Leukotrienes (LTs)
Section 2
Metabolism of Triglycerides
Triglyceride (TG) or triacylglycerol (TAG)
Glycerol
O
O
1
CH2 O C R1
2
R2 C O C H
3
O
CH2 O C R3
Overview of triglycerides metabolism
Triglycerides
(fats)
Lipolysis
Esterification
Diet
Fatty acids
Lipogenesis
Carbohydrate
Amino acids
Steroids
¦Â-Oxidation
Steroidogenesis
Acetyl-CoA
Cholesterol
CholesteroloKe
genesis
tog
en
es
TAC
is
Ketone bodies
2CO2
§ 2.1 Degradation of TG
§ 2.1.1 Fat catabolism (lipolysis)
§ 2.1.2 β-Oxidation of Fatty acids
§ 2.1.3 Other Oxidations of Fatty acids
§ 2.1.4 Ketone Bodies Formation and
Utilization
§ 2.1.1 Fat catabolism (lipolysis)
Fat mobilization：
The triacylglycerol stored in the
adipocytes are hydrolyzed by lipases,
to produce free fatty acids (FFA) and
glycerol, which are released to the
blood, this process is called fat
mobilization.
The fatty acids thus released
diffusively from the adipocyte into the
blood, where they bind to the serum
albumin.
Hormone sensitive lipase (HSL)
• TG lipase is the rate-limiting enzyme in
the TG degradation in adipose tissue. It
is also named HSL because it is
regulated by some hormones.
Effect of hormones on lipolysis
• Lipolytic Hormones:
epinephrine
norepinephrine
adrenocorticotropic hormone (ACTH)
thyroid stimulating hormone (TSH)
Glucagon etc.
• Antilipolytic Hormones: insulin
glycerol metabolism
Place: liver, kidney, intestine
g
ADP
CH2OH
CH2OH ATP
3-phlycerol
deh osph
yd r o
HO C H
a
HO C H
g en t e
glycerol
as e
CH2O P
kinase
CH2OH
NAD+
CH2OH
Glycerol
L-Glycerol
3-phosphate
O C
NADH+H+
Glycolysis
CHO
H C OH
Glyconeogenesis
CH2O P
D-Glyceraldehyde
3-phosphate
CH2O P
Dihydroxyacetone
triose
phosphate
phosphate
isomerase
Note
• In muscle cells and adipocytes, the
activity of glycerol kinase is low, so
these tissues cannot use glycerol as
fuel.
§ 2.1.2 β-Oxidation of Fatty
acids
• Fatty acids are one of the main
energy materials of human and other
mammalian.
• Fatty acid catabolism can be
subdivided into 3 stages.
Stage 1 Activation of FAs
• Acyl-CoA Synthetase (Thiokinase), which
locates on the cytoplasm, catalyzes the
activation of long chain fatty acids.
O
R C
+ HSCoA
O
Fatty acid
AMP + PPi
O
Mg2+
R C
acyl-CoA
S CoA
synthetase
acyl-CoA
ATP
Key points of FA activation
1. Irreversible
2. Consume 2 ~P
3. Site: cytosol
Stage 2
Transport of acyl CoA into the
mitochondria
( rate-limiting step)
• Carrier: carnitine
Rate-limiting enzyme
• carnitine acyltransferase Ⅰ
CH3
OH
+
H3C N CH2 CH CH2 COO
CH3
Carnitine
CH3
+
H3C N CH2
CH3
C
O
SCoA
carnitine
acyltransferase ¢ñ
R
C
R
O
O

CH CH2 COO
Fatty acyl carnitine
HSCoA
Stage 3: β-oxidation of FAs
β-oxidation means β-C reaction.
Four steps in one round
step 1: Dehydrogenate
step 2: Hydration
step 3: Dehydrogenate
step 4: Thiolytic cleavage
Step 1. Dehydrogenate
H3C
H
H
O
C
C
C
H
FAD
H
(CH2)n


SCoA
Fatty acyl-CoA
acyl-CoA dehydrogenase
FADH2
H3C
(CH2)n
C
H
H
O
C
C
SCoA
trans-¦¤2-enoyl-CoA
Step 2. Hydration
H3C
(CH2)n
C
H
O
C
C
Trans-¦¤2-enoyl-CoA
H
H2O
H3C
(CH2)n
SCoA
enoyl-CoA Hydratase
OH H
O
C
C
C
H
H
3-L-Hydroxyacyl-CoA
SCoA
Step 3. Dehydrogenate
H3C
OH H
O
C
C
C
H
NAD+
H
3-L-Hydroxyacyl-CoA
(CH2)n
NADH + H+
hydroxyacyl-CoA
dehydrogenase
O
H3C
(CH2)n
C
SCoA
O
CH2
C
SCoA
β-Ketoacyl-CoA
Step 4. Thiolytic cleavage
O
H3C
(CH2)n
C
O
CH2
C
SCoA
β-Ketoacyl-CoA
HSCoA
β-Ketothiolase
O
H3C
(CH2)n
C
O
SCoA + CH3
Fatty acyl-CoA
(2C shorter)
C
SCoA
Acetyl-CoA
β- oxidation of fatty acids
The β-oxidation pathway is cyclic
Summary
one cycle of the β-oxidation:
fatty acyl-CoA + FAD + NAD+ + HS-CoA
→fatty acyl-CoA (2 C less) + FADH2 +
NADH + H+ + acetyl-CoA
The product of the
β-oxidation is in
the form of FADH2,
NADH, acetyl CoA,
only after Krebs
cycle and
oxidative
phosphorylation,
can ATP be
produced.
Energy yield from one molecule of palmitic acid
palmitic acid
-2 ~P activation
7¡Á
2
respiratory chain
8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+
palmitoyl-CoA
7 turns of
¦Â-oxidation
TAC
respiratory chain
8¡Á
12
7¡Á
3
The net ATP production: 131－2 = 129
§ 2.1.3 Other Oxidations of
Fatty acids
1. Oxidation of unsaturated fatty acids
2. Peroxisomal fatty acid oxidation
3. Oxidation of propionyl-CoA
1. Oxidation of unsaturated fatty acid
• Mitochondria
• Isomerase: cis → trans
• Epimerase: D (-) → L (+)
2. Peroxisomal fatty acid oxidation
Very long chain fatty acids
FAD
Acyl-CoA oxidase
shorter chain fatty acids
β-oxidation
3. Oxidation of propionyl-CoA
propionyl-CoA
Carboxylase (biotin)
Epimerase
Mutase (VB12)
succinyl-CoA
§ 2.1.4 Ketone Bodies
Formation and Utilization
• Ketone bodies are water-soluble
fuels normally exported by the liver
but overproduced during fasting or
in untreated diabetes mellitus,
including acetoacetate, βhydroxybutyrate, and acetone.
The formation of ketone bodies
(Ketogenesis)
Location: hepatic mitochondria
Material: acetyl CoA
Rate-limiting enzyme: HMG-CoA
synthase
O
CH3
C S CoA
HSCoA
O
+
CH3
2 Acetyl-CoA
O
CH3
C S CoA
thiolase
O
C CH2 C S CoA
Acetoacetyl-CoA
HMG-CoA
synthase
OH
OH
CH3
OOC CH2
CH CH2 COO
HSCoA
O
C CH2 C S CoA
CH3
¦Â-Hydroxy-¦Â-methylglutaryl-CoA
¡¡ ¡¡ ¡¡ ¡¡ £¨ HMG-CoA£©
¦Â-Hydroxy-butyrate
NAD+
¦Â-hydroxybutyrate
dehydrogenase
NADH+H+
HMG-CoA
lyase
O
Acetyl-CoA
O
CH3 C CH3
Acetone
Acetyl-CoA
CH3
CO2
C CH2 COO
Acetoacetate
Utilization of ketone bodies (ketolysis) at
extrahepatic tissues
Succinyl-CoA
transsulfurase
HSCoA
ATP
-
AMP
PPi
Acetoacetate
thiokinase
Lack of succinyl-CoA transsulfurase
and Acetoacetate thiokinase in the liver.
Biological Significance
• Ketone bodies replace glucose as the
major source of energy for many
tissues especially the brain, heart and
muscles during times of prolonged
starvation.
Normal physiological responses to
carbohydrate shortages cause the
liver to increase the production of
ketone bodies from the acetyl-CoA
generated from fatty acid oxidation.
Hepatocyte
Acetoacetate,
β-hydroxybutyrate,
acetone
Ketone
body
formation
Fatty
Acetyl-CoA
acids
β-oxidation
CoA
Citric
Acid cycle
Ketone bodies
exported as
energy source
for heart,
skeletal muscle,
kidney, and
brain
oxaloacetate
gluconeogenesis
Glucose
Glucose exported
as fuel for tissues
such as brain
Plasma concentrations of metabolic fuels
(mmol/L) in the fed and starving states
Ketosis consists of ketonemia, ketonuria
and smell of acetone in breath
Causes for ketosis
• Severe diabetes mellitus
• Starvation
• Hyperemesis (vomiting) in early
pregnancy
§ 2.2 Lipogenesis
§ 2.2.1 Synthesis of fatty acid
O
C-S-CoA
H3C
palmitic acid (C16:0)
palmitoylCoA
O
C-S-CoA
H3C
stearic acid (C18:0)
stearoylCoA
O
C-S-CoA
9
oleic acid (C18:1 D9)
18
H3C
1
oleoylCoA
1. Palmitic Acid Synthesis
Location: cytosol of liver, adipose tissue,
kidney, brain and breast.
Precursor: acetyl CoA
Other materials: ATP, NADPH, CO2
Citrate-pyruvate cycle
mitochondrion
Acetyl CoA
citrate
TCAC
cytosol
Acetyl CoA
citrate
oxaloacetate
NADH
oxaloacetate
malate
malate
NADPH
pyruvate
pyruvate
CO2
glucose
The sources of NADPH are as follows:
• Pentose phosphate pathway
• Malic enzyme
• Cytoplasmic isocitrate dehydrogenase
Process of synthesis:
(1) Carboxylation of Acetyl CoA
(2) Repetitive steps catalyzed by fatty
acid synthase
(1) Carboxylation of Acetyl CoA
O
CH3 C SCoA + HCO3
acetyl-CoA
ATP
ADP + Pi
biotin
acetyl-CoA
carboxylase
O
OOC CH2 C SCoA
malonyl-CoA
Malonyl-CoA serves as the donor of twocarbon unit.
Acetyl-CoA Carboxylase is the rate
limiting enzyme of the fatty acid
synthesis pathway.
The mammalian enzyme is regulated, by
 phosphorylation
 allosteric regulation by local
metabolites.
glucagon
ATP
insulin
ADP + Pi
acetyl-CoA + HCO3 + H+
malonyl-CoA
acetyl-CoA carboxylase
(biotin)
long chain acyl-CoA
citrate
isocitrate
(2) Repetitive steps catalyzed by
fatty acid synthase
Fatty acid synthesis from acetyl-CoA &
malonyl-CoA occurs by a series of
reactions that are:
 in bacteria catalyzed by seven separate
enzymes.
 in mammals catalyzed by individual
domains of a single large polypeptide.
Fatty acid synthase complex
(multifunctional enzyme)
•
•
•
•
•
•
•
•
Acyl carrier protein (ACP)
Acetyl-CoA-ACP transacetylase (AT)
β-Ketoacyl-ACP synthase (KS)
Malonyl-CoA-ACP transferase (MT)
β-Ketoacyl-ACP reductase (KR)
β-Hydroacyl-ACP dehydratase (HD)
Enoyl-ACP reductase (ER)
Thioesterase (TE)
AT
MT
HD
Cys
Subunit
division
HS
HS
KR
ACP
Functional
division
KS
ER
TE
PhP
HS
HS
PhP
Cys
TE
KS
ACP
KR
ER
HD
MT
AT
ACP contains 4’-phosphopantotheine.
O
HS
CH3 C S
CH 3 C S CoA
O
HS
HS
ACP-HS
KS-HS
OOC CH 2 C S CoA
O
HS CoA
O
MT
AT
HS CoA
OOC CH2 C S
CH3 C S
O
O
CH3 (CH2)14 C O
O
(After 7 rounds)
HS
CH3 CH2 CH2 C S
TE
H2O
①
condensation KS
CO 2
O
O
CH3 C CH2 C S
HS
O
AT
CH3 CH2 CH2 C S
HS
②
④
O
reduction
NADP+
CH3 CH CH2 C S
HS
OH
ER
O
NADPH + H+
CH3 CH CH C S
HS
reduction
③
dehydration
HD
H2O
KR
NADPH
+ H+
NADP+
The overall reaction of synthesis:
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+
palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O
Differences in the oxidation and synthesis of FAs
β-oxidation
Fatty acid synthesis
Site
Mitochondria
Cytoplasm
Intermediates
Present as CoA
derivatives
Covalently linked to SH
group of ACP
Enzymes
Present as
independent proteins
Multi-enzyme complex
Sequential
units
2 carbon units split off 2 carbon units added, as 3
as acetyl CoA
carbon malonyl CoA
Co-enzymes
NAD+ and FAD are
reduced
NADPH used as reducing
power
Routes of synthesis of other fatty acids
2. Elongation of palmitate
Elongation beyond the 16-C length of
the palmitate occurs in mitochondria
and endoplasmic reticulum (ER).
 Fatty acid elongation within
mitochondria uses the acetyl-CoA as
donor of 2-carbon units and NADPH
serves as electron donor for the final
reduction step.
 Fatty acids esterified to coenzyme A
are substrates for the ER elongation
machinery, which uses malonyl-CoA as
donor of 2-carbon units.
3. The synthesis of unsaturated
fatty acid
• Formation of a double bond in a fatty
acid involves several endoplasmic
reticulum membrane proteins in
mammalian cells
O
10 9
oleate 18:1 cis D9
C
OH
Desaturases introduce double bonds at
specific positions in a fatty acid chain.
§ 2.2.2
Synthesis of Triacylglycerol
• Monoacylglycerol pathway (small
intestine)
• Diacylglycerol pathway (liver, adipose
tissue)
1. Monoacylglycerol pathway
O
O
CH2
HSCoA
OH acyl CoA
R2 C O C H
CH2
OH
acyl CoA
transferase
O
CH2
R2 C O C H
CH2
O
acyl CoA
transferase
C R1
OH
1,2-diacylglycerol
2-monoacylglycerol
HSCoA
acyl CoA
O
O
CH2 O C R1
R2 C O C H
O
CH2 O C R3
triacylglycerol
2. Diacylglycerol pathway
glycolysis
Summary
• Places:
tissue
small intestine, liver, adipose
• Materials:
Endogenous: glucose、amino acid、
glycerol
Exogenous: free fatty acid and
monoacylglycerol
Adipose tissue generate fat mainly from
glucose
• In adipose tissue, the acetyl CoA for the
synthesis of fatty acid is mainly from
glucose.
• The lack of glycerol kinase make the only
source of glycerol 3-phosphate in
adipose tissue is glucose.
Obesity results from an imbalance between
energy input and output
Food
adipose
tissue
Work
or
Growth
fatty acids
& triacylglcerols
ADP
ATP
Heat
CO2 + H2O
Obesity
Section 3 Metabolism of
Phospholipids
• Phospholipid refers to phosphorouscontaining lipids.
Glycerophospholipids
Phospholipids
Sphingolipids
§ 3.1 Classification and Structure of
Glycerophospholipids
• Glycerophospholipids are lipids with a
glycerol, fatty acids, a phosphate group
and a nitrogenous base.
glycerol
fatty acids
nitrogenous base
Phosphatidylcholine
甘油
glycerol
脂酰基
CH2 O
O
R2
C
O
O
fatty acyl group
C
CH2
H
C
R1
脂酰基
fatty
acyl group
O
O
P
含氮化合物
O X Nitrogenous
base
OH
The basic structure of glycerophospholipid
In general, glycerophospholipids
contain a saturated fatty acid at C-1 and
an unsaturated fatty acid (usually
arachidonic acid) at C-2.
The major
function of
phospholipids
is to form
biomembrane.
• Hydrophobic tail = fatty acids
• Polar head = nitrogenous base
Some common glycerophospholipid
Some common glycerophospholipid
(continue)
§ 3.2
Synthesis of Glycerophospholipid
Location:
All tissue of body, especially liver &
kidney
Endoplasmic reticulum
Pathways:
CDP-diacylglycerol pathway
Diacylglycerol pathway
The system of synthesis
a. FA
Glycerol
from carbohydrate
b. poly unsaturated fatty acid from plant oil
c. choline
ethanolamine
serine
inositol
from food or synthesis
in body
d. ATP, CTP
e. Enzymes and cofactors
Diacylglycerol pathway
CO2
HO CH2 CH COOH
HO CH2 CH2 NH2
3 SAM
HO CH2 CH2 N(CH3)3
Choline
Ethanolamine
NH2
Serine
ATP
ATP
ADP
ADP
P O CH2 CH2 N(CH3)3
P O CH2 CH2 NH2
Phosphocholine
Phosphoethanolamine
CTP
CTP
PPi
PPi
CDP O CH2 CH2 NH2
CDP O CH2 CH2 N(CH3)3
CDP-choline
CDP-ethanolamine
CO2
Phosphatidyl
serine
DG
DG
CMP
CMP
Phosphatidyl
ethanolamine
3 SAM
Phosphatidyl
choline
CDP-Diacylglycerol pathway
Dihydroxyacetone
phosphate
Glycerol 3-phosphate
Phosphotidate
CTP
G
PPi
CDP-diacylglycerol
Inositol
CMP
Serine
Phosphatidyl glycerol
CMP
CMP
Phosphatidyl inositol
Diphosphatidyl glycerol
(cardiolipin)
Phosphatidyl serine
Phosphatidylcholine (Lecithin)
Phosphatidylethanolamine (Cephalin)
CDP-diacylglycerol
Phosphatidylserine
Phosphatidylglycerol
Diphosphatidyl glycerol
(Cardiolipin)
Phosphatidylinositol
§ 3.3 Degradation of
glycerophospholipids by
phospholipase
A1
O
A2
O
R2
C
O
O
CH2
C
CH2
C
R1
D
H
O
O
P
OH
C
O
X
O
O
CH2
HO
C
CH2
H
C
R1
R2
B1 O
O
P
O
OH
Lysophospholipid-1
X
C
OH
CH2
O
O
B2
C
CH2
H
O
O
P
OH
Lysophospholipid-2
O
X
Actions of phospholipases on
lecithin
• PLA1: fatty acid + lysolecithin
• PLA2: fatty acid + acyl
glycerophosphoryl choline
• PLC: 1,2 diacylglycerol + phosphoryl
choline
• PLD: phosphatidic acid + choline
Lysophospholipids, the products of
Phospholipase A hydrolysis, are
powerful detergents.
O
O
O
R2
C
CH2
O
C
H
O C
R1 H2O
R2
P
O
phospholipid
O
CH2
HO
O
PLA2
CH2O
C
O
O X
C
O
H
O
CH2O
P
C
R1
O X
O
Lysophospholipid
Section 4 Metabolism of
Cholesterol
§ 4.1 Structure and function of
cholesterol
1. Function of cholesterol:
(1) It is a constituent of all cell
membranes.
(2) It is necessary for the synthesis of all
steroid hormones, bile salts and
vitamin D.
2. Structure of cholesterol
All steroids have cyclopentano penhydro
phenanthrene ring system.
H3C 21
22
18 CH3
12
19 CH3
1
2
HO
4
C
9
10
A
3
11
5
B 8
6
7
23
24
25
CH3
20
27 CH3
17
13
D 16
14
15
26
Cholesterol ester
O
C
R
O
§ 4.2 Synthesis of cholesterol
Location:
• All tissue except brain and mature red
blood cells.
• The major organ is liver (80%).
• Enzymes locate in cytosol and
endoplasmic reticulum.
Materials:
Acetyl CoA, NADPH(H+), ATP
Acetyl-CoA is the direct and the only carbon
source.
Acetyl-CoA
HMG-CoA
Acetoacetyl-CoA
HMG CoA reductase is the rate-limiting enzyme
The total process of cholesterol de novo synthesis
Regulation of cholesterol synthesis
fasting
HMG CoA
Glucagon
HMG CoA reductase
after meal
insulin
MVA
thyroxine
cholesterol
bile acid
§ 4.3 Transformation and excretion
of cholesterol
Bile acids
Steroid
hormones
Vitamin D
Cholesterol
1. Conversion of Cholesterol into
bile acid
(1) Classification of bile acids
The primary bile acids are synthesized in
the liver from cholesterol. The 7hydroxylase is rate-limiting enzyme in
the pathway for synthesis of the bile
acids.
The secondary bile acids are products
that the primary bile acids in the
intestine are subjected to some further
changes by the activity of the intestinal
bacteria.
Classification of bile acids
Classification
Free bile
acids
Cholic acid
Glycocholic
acid
Taurocholic acid
Chenodeoxycholic acid
Glycochenodeoxycholic
acid
Taurochenodeoxycholic acid
Deoxycholic
acid
Glycodeoxycholic acid
Taurodeoxycholic acid
Lithocholic
acid
Glycolithocholic acid
Taurolitho-cholic
acid
Primary bile
acids
Secondary
bile acids
Conjugated bile acids
(2) Strcture of bile acids
OH
COOH
COOH
12
3
HO
7
H
cholic acid
OH
OH
HO
H
OH
glycocholic acid
HO
OH
H
chenodeoxycholic acid
CONHCH2COOH
HO
OH
H
CONHCH2CH2SO3H
OH
taurocholic acid
OH
HO
H
deoxycholic acid
COOH
COOH
HO
H
lithocholic acid
(3) Enterohepatic Cycle of bile
acids
Conversion to bile salts, that are
secreted into the intestine, is the only
mechanism by which cholesterol is
excreted.
Most bile acids are reabsorbed in the
ileum , returned to the liver by the portal
vein, and re-secreted into the intestine.
This is the enterohepatic cycle.
(4) Function of bile acids
Bile acids are amphipathic, with
detergent properties.
• Emulsify fat and aid digestion of fats &
fat-soluble vitamins in the intestine.
• Increase solubility of cholesterol in bile.
2. Conversion of cholesterol into
steroid hormones
• Tissues: adrenal cortex, gonads
• Steroid hormones: cortisol (glucocorticoid), corticosterone and aldosterone
(mineralocorticoid), progesterone,
testosterone, and estradiol
Steroids derived from cholesterol
3. Conversion into 7-dehydrocholesterol
cholesterol
£¨ in skin£©
25-hydroxylase
(microsome
in the liver)
ultraviolet
light
7-dehydrocholecalciferol (VD3)
cholesterol
25-OH-D3
1¦Á-hydroxylase
(mitochondria
in the kidney)
1,25-(OH)2-D3
£¨ active Vit D3£©
§ 4.4 Esterification of cholesterol
• in cells
SHCoA
acyl CoA
O
HO
cholesterol
acyl CoA
cholesterol R C O
acyl transferase
cholesteryl ester
(ACAT)
in plasma
Section 5
Plasma lipoprotein
§ 5.1 blood lipid
• Concept: All the lipids contained in
plasma, including fat, phosphalipids,
cholesterol, cholesterol ester and fatty
acid.
• Blood lipid exist and transport in the
form of lipoprotein.
TG
cholesterol
blood lipids
free
ester
lecithin
phospholipids sphingolipids
cephalin
FFA
§ 5.2 Classification of plasma
lipoproteins
1. electrophoresis method:
- Lipoprotein
fast
pre -Lipoprotein
-Lipoprotein
CM (chylomicron)
slow
2. Ultra centrifugation method：
high density lipoprotein (HDL)
high
low density lipoprotein ( LDL)
very low density lipoprotein ( VLDL)
CM (chylomicron )
low
electron microscope
CM
LDL
VLDL
HDL
－
＋
Origin
CM

Pre-

Separation of plasma lipoproteins by
electrophoresis on agarose gel
§ 5.3 Structure
§ 5.4 Composition of lipoprotein
CM
VLDL
LDL
HDL
<1.006
0.951.006
1.0061.063
1.0631.210
Protein
2
10
23
55
Phospholipids
9
18
20
24
Cholesterol
1
7
8
2
Cholesteryl esters
3
12
37
15
TG
85
50
10
4
Density(g/ml)
§ 5.5 Apolipoproteins
Functions of apolipoproteins
a . To combine and transport lipids.
b . To regulate lipoprotein metabolism.
apo A II activates hepatic lipase（HL）
apo A I activates LCAT
apo C II activates lipoprotein lipase
（LPL）
c. To recognize the lipoprotein receptors.
§ 5.6 Metabolism of plasma
lipoprotein
1. CM
• Chylomicrons are formed in the
intestinal mucosal cells and secreted
into the lacteals of lymphatic system.
structure of CM
Apolipoproteins
phospholipids
Cholesterol
Triacylglycerols and
cholesteryl esters
Metabolic fate of CM
summary of CM
• Site of formation: intestinal mucosal
cells
• Function: transport exogenous TG
• key E: LPL in blood
HL in liver
• apoCⅡ is the activator of LPL
• apo E and apo B-48 will be recognized
by the LRP receptor
2. VLDL
• Very low density lipoproteins (VLDL)
are synthesized in the liver and
produce a turbidity in plasma.
Nascent
VLDL
Metabolic fate of VLDL and production of LDL
Summary of VLDL
• Formation site: liver
• Function: VLDL carries endogenous
triglycerides from liver to peripheral
tissues for energy needs.
• key E: LPL in blood
HL in liver
3. LDL
• Most of the LDL particles are derived
from VLDL, but a small part is directly
released from liver. They are
cholesterol rich lipoprotein molecules
containing only apo B-100.
LDL
receptors
Cholesterol
ester
protein
Cholesterol
LDL
Cholesteryl
oleate
Amino acids
LDL binding
Internalization
Lysosomal hydrolysis
Michael Brown and
Joseph Goldstein
were awarded Nobel
prize in 1985 for their
work on LDL
receptors.
Summary of LDL
• Formation site: from VLDL in blood
• Function: transport cholesterol from
liver to the peripheral tissues. LDL
concentration in blood has positive
correlation with incidence of
cardiovascular diseases.
Fates of cholesterol in the cells
1. Incorporated into cell membranes.
2. Metabolized to steroid hormones.
3. Re-esterified and stored. The reesterification is catalyzed by ACAT.
4. Expulsion of cholesterol from the cell,
esterified by LCAT and transported by
HDL and finally excreted through liver.
4. HDL
• LDL variety is called “ bad cholesterol”
whereas HDL is known as “ good
cholesterol” .
Liver
Heart
VLDL
“Good”
Excretion
“BAD”
LDL
Cholesterol
Deposit
HDL
Forward and reverse cholesterol transport
Reverse cholesterol transport
• Cholesterol from tissues reach liver,
and is later excreted. This is called
reverse cholesterol transport by HDL.
Metabolism of HDL in reverse cholesterol transport
CETP
• Cholesterol ester transfer protein
(CETP) transfer cholesterol ester in
HDL to VLDL and LDL.
Summary of HDL
• Formation site: liver and intestine
• Function: transport cholesterol from
peripheral tissues to liver
summary of lipoprotein metabolism
§ 5.7 Hyperlipidemias
classification
Lipoprotein
Blood lipids
Ⅰ
CM
TAG↑ ↑ ↑ CH↑
Ⅱa
LDL
CH↑ ↑
Ⅱb
LDL, VLDL
CH↑ ↑ TAG↑ ↑
Ⅲ
IDL
CH↑ ↑ TAG↑ ↑
Ⅳ
VLDL
Ⅴ
VLDL, CM
TAG↑ ↑
TAG↑ ↑ ↑ CH↑