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Metabolism of Lipids
Haibin Tian
[email protected]
Fatty liver
Obesity
Lipid
metabolism
disorder
Hyperlipoidemia
Arteriosclerosis
Contents
Concept, classification and structure of lipid
Metabolism: Decomposition and biosynthesis
The factors regulating lipid metabolism
Section 1 Introduction of lipid
Classfication and structure
Distribution and function
Digestion and absorption
1. Classfication and structure
Lipids are substances that are insoluble in water but soluble in
organic solvents.
Fat (Triacylglycerol)
Glycerophospholipids
Phospholipids
Lipid
Sphingophospholipids
Glycolipid
lipoid
Cholesterol
Cholesteryl ester
Fat
Fat：Triacylglycerols (TAG), esters of fatty
acids with glycerol
Structure of triacylglycerol
Glycerol has three hydroxyl groups and can form
esters with three fatty acid.
 Fatty acids in TG are not always identical
O
Glycerol
FA
O
FA
H3C (CH2)n C
FA
H2 C
O
O
CH
H2 C
C (CH2)m CH3
O
O
C (CH2)k
CH3
Fatty acid： Fatty acids are carboxylic acids with
hydrocarbon chains and carboxylic group
The predominate fatty acid residues in plants and
animals are C16 and C18
Common fatty acid
Saturated fatty
acid
Unsaturated
fatty
acid
Unsaturated fatty acid nomenclature
△nomenclature, Indicating the number
and position of double bonds counting from
carboxylic group
ω or n nomenclature, Indicating
the
number and position of double bonds
counting from methyl group
15
12
9
△
20:4 △5C,8C,11C,14C
20:4 ω 6C,9C,12C,15C
Essential Fatty Acids(EFA):
Some fatty acids that are necessary for human
nutrition, but can’t synthesis in the body, must
obtain from food .
Including:
(18:2)
(18:3)
Lipoid
Lipoid includes phospholipids、 glycolipids、
cholesterol and cholesteryl ester
 Phospholipids: Lipids containing fatty acids and a
phosphoric acid residue.
 Glycolipids: lipids containing carbohydrate
 Cholesterol: Forming ester by hydroxyl group
Phospholipids
Glycerophospholipids
O
O
H2C
H3C (CH2)n C O
O
CH
H2C
C
(CH2)m CH3
O
O
P
O
X
OH
X = Choline、Ethanolamine、
serine 、 myoinositol 、
Phosphatidylglycerol
Sphingophospholipids
Amido bond
Creamide
X = Choline、Ethanolamine、
Cholesteryl ester
Cholesterol
FA
Cholesterol
Classfication and structure
Fat (Triacylglycerols)
Glycerophospholipids
Phospholipids
Lipid
Sphingophospholipids
Glycolipid
lipoid
Cholesterol
Cholesteryl ester
2. Lipid distribution and function
Fat：Exists with small oil drips in the cytoplasm of
adipocytes in vertebrates
Fat is also called as variable fat
lipoid： Structure components of biomembranes
 lipoid is also called as fixed lipid
Functions of fat
1) Energy storage
2) Prevent body from heat lose
Functions of lipoid
Structure components of biomembranes
Material for steroid-hormones, bile acid, and
Vitamin A、D、E、K
3. Digestion and absorption of
Lipids
The site of digestion:
duodenum, small intestine
Condition:
1. bile salts (emulsification)
2. lipolytic enzymes
Pancreatic lipase
Phospholipase A2
Cholesteryl esterase
Process of digestion ：
bile salts
Food lipids
particles
small
pancreatic lipase（ colipase,
）
triglyceride
2monoacylglycerol + 2FFA
phospholipase A2
phospholipid
lysophosphatide + FFA
Emulsification
 Bile acts to some extent as a
surfactant, helping to
emulsify the fats in the food.
Bile salt anions have a
hydrophilic side and a
hydrophobic side, and
therefore tend to aggregate
around droplets of fat
(triglycerides and
phospholipids) to form
micelles, with the
hydrophobic sides towards
the fat and hydrophilic
towards the outside.
Process of digestion ：
bile salts
Food lipids
particles
small
pancreatic lipase（ colipase,
）
2-单酰甘油
triglyceride
2monoacylglycerol + 2FFA
溶血磷
phospholipase
A2
脂
phospholipid
lysophosphatide + FFA
Colipase
Duodenum
pancreatic acini
Proenzyme
Trypsin
Colipase
Pentapeptide
Binding pancreatic lipase
Trigger lipase activity
Process of digestion ：
bile salts
Food lipids
particles
small
pancreatic lipase（ colipase
）
triglyceride
2monoacylglycerol + 2FFA
phospholipase A2
phospholipid
lysophosphatide + FFA
Absorption of lipids：
Medium(6-10C) and short chain (2-4C) triglyceride
Emulsification by bile
salts
Intestine mucosal cells
Degradated by lipase
FFA and
glycerol
portal
vein
transport
blood
circulation
epithelial cells （to
Long chain fatty acids (1226C)+monoacylglycerol
synthesize TG）
epithelial cells （to
synthesize CE）
cholesterol + FFA
epithelial cells （to
synthesize PL）
lysophosphatide + FFA
TG、CE、PL
blood
circulation
lymphatic
system
+
Apo（载脂蛋白）
(chylomicron, CM,)
Contents of lipid
metabolism
Concept, Classfication and Structure of Lipids
Degradation and Biosynthesis of Lipids
Factors Regulating Lipid Metabolism
Section 2. Fat metabolism
1. Fat mobilization and hydrolysis
2. Fatty acid β-oxidation
3. Ketone body formation
4. Fat synthesis
Fatty acid and glycerol synthesis
1. Fat mobilization and hydrolysis
Fat mobilization (Lipolysis）:
The TG stored in the adipocytes are hydrolyzed
by hormone-sensitive triacylglycerol lipase (HSL),
produce free fatty acids (FFA) and glycerol, which
are released into the blood, these process is called as
fat mobilization.
Process：
TG lipase
TG
DG lipase
DG
FFA
Glycerol
FA
FA
FA
MG lipase
MG
FFA
glycerol
FFA
TG------triacylglycerol
DG------diacylglycerol
MG-----monoacylglycerol
Lipase
Hormone-sensitive lipase (HSL)
 HSL is expressed in all the tissues, but mainly in
fat tissue
HSL can also act on Cholesteryl ester
Pancreatic lipase ： Digestive tract
Lysosomal lipase ： Lysosome
Lipoprotein lipase ：Blood
 Hepatic lipase ：Liver
Regulation of HSL by hormone
Lipolytic hormones : stimulate TG hydrolysis
Glucagons
Adrenocorticotropic hormone (ATCH)
Epinephrine
Norepinephrine
Anti-lipolytic hormones: inhibit TG hydrolysis
Insulin
Regulation of HSL by hormone
Lipolysis is
activated
when we are
in hungry
and excited
state
Section 2. Fat metabolism
1. Fat mobilization and hydrolysis
2. Fatty acid β-oxidation
3. Ketone body formation
4. Fat synthesis
Fatty acid and glycerol synthesis
2. Beta-Oxidation of fatty acids
Fatty acids show a lower solubility in water and are
combined with serum albumin when transferred in
plasma
Fatty acids are oxidized to acetyl-CoA in all tissues
except for brain and erythrocyte
Fatty acid oxidation was found to occur in
mitochondria
FAs are the major energy source of human
of the biologically available energy in TGs:
~ 95 % in their 3 long-chain FA
~ 5% in their glycerol
Step 1 Fatty acid’s activation

On the outer membrane of mitochondria

Fatty acids are converted to fatty acyl-CoA (a high energy
compound) via a fatty-acyl-adenylate intermediate by the
action of fatty acyl-CoA synthetase (also called fatty acid
thiokinase).

Pyrophosphate is hydrolyzed by inorganic pyrophosphatase
Fatty
脂 肪acid
酸
ATP
O
RCH2CH 2C~SCoA
Acyl-CoA
脂
酰~SCoA
AMP +PPi
=
=
O
RCH2CH2C-OH + CoA-SH
Acyl CoA
synthetase
Step 2 Activated fatty acids are carried into
the matrix by Carnitine
Mitochondria consists of outer and inner membranes
Permeability of outer membrane allows passage of
molecules of 5000 Daltons or less, semipermeability of
inner membrane allows passage of only small molecules
Carnitine -Acylcarnitine
3-hydroxy-4-(trimethylammonio)butyrate
Transport of Acyl-CoA into mitochondria
:
Carnitine acyltransferase I
Carnitine acyltransferase II
Carnitine/acylcarnitine transporter
Carnitine acyltransferase I
Transport of Acyl-CoA into mitochondria is the ratelimiting step for oxidation of fatty acids
Carnitine acyltransferase I is the rate-limiting enzyme
Malonyl-CoA is allosteric inhibitor of carnitine
acyltransferase I. Insulin inhibits oxidation of fatty acids
by promoting malonyl-CoA synthesis
Insulin
activate
Carboxylase
Acetyl-CoA
Malonyl-CoA
Carnitine
acyltransferase I
Supplementary Information：
Carnitine – losing weight？
Diet pills on the market
No strong evidence shows carnitine
can reduce body weight
Reasons
Rate-limiting enzyme？
Food？
Energy demand？
Step3. β-oxidation of Acyl CoA
Early labeling experiments (1904): fatty acids are
degraded by sequential removal of two-carbon units
Franz Knoop’s
labeling
Experiments
(1904):
fatty acids are
degraded by
oxidation at the βcarbon, i.e.,
β-oxidation
β-oxidation of Acyl-CoA
1.
Dehydrogenation
2.
Hydration
3.
Dehydrogenation
4.
Thiolysis
Dehydrogenation
Fatty acyl-CoA
Enoyl-CoA
Hydration
enoyl-CoA
β -hydroxylacyl-CoA
Dehydrogenation
b -hydroxylacyl-CoA
ketoacyl-CoA
Thiolysis
ketoacyl-CoA
thiolase
Fatty acyl-CoA
Four steps in one cycle ：
=
O
RCH2CH2C~SCoA
Dehydrogenation
FAD
FADH2
acyl CoA
dehydrogenase
α O
=
β
RCH=CHC~SCoA
Hydration
H2 O
⊿2-- enoyl-CoA
hydratase
Dehydrogenation
α
=
O
RCHOHCH2C~SCoA
β
L(+)- β-hydroxyacyl CoA
dehydrogenase
NAD+
NADH+H+
=
β α O
RCOCH2C~SCoA
Thiolysis
β-ketoacyl-CoA
CoA-SH
=
O
RC~SCoA + CH3CO~SCoA
Energy calculate (ATP amount)
1 C16
1 molecule of palmitoyl-CoA
2
（16C） will pass through the
3
sequence 7 times, eventually
be oxidized to produce:
8 Acetyl CoAs
7 NADHs
7 FADH2s
4
5
6
7
Acetyl -CoA
7× FADH2：
7×1.5
7×NADH2:
7×2.5
8×acetyl CoA： 8×10
Activation of FA consuming 2ATP
Totally: (7×1.5)+(7×2.5)+(8×10)-2 =106
β-oxidation of the odd-chain fatty acids
 β-oxidation of the odd-chain
fatty acids, which are relatively
rare in nature, produce a
propionyl CoA in the final
round.
 Propionyl- CoA can be
converted to via a carboxylation,
an epimerization and an
intramolecular group shifting.
β-oxidation of unsaturated fatty acids
Accessory enzymes are required for dealing
with fatty acids having double bonds. Basically
the cis double bonds in unsaturated fatty acids
have to be converted to trans double bonds to
allow beta oxidation to continue.
Beta oxidation of unsaturated fatty acids
Isomerase (异构酶) and a reductase (还原酶) are needed for
oxidizing a unsaturated fatty acid.
Significance of β-oxidation :
Provide energy: The oxidation of fatty acids yields
significantly more energy per carbon atom than does
the oxidation of carbohydrates.
Provide acetyl CoA ( then into TCA cycle, ketone
bodies, cholesterol and FA);
Fat metabolism
(脂肪代谢)
1. Fat mobilization and hydrolysis
脂肪的动员和水解
2. Fatty acid β-oxidation
脂肪酸β-氧化
3. Ketone body formation
酮体产生
4. Fatty acid synthesis
脂肪酸合成
5. Fat synthesis
脂肪合成
3. Ketone body formation and utilization
Concept:
The special intermediate products of β-oxidation of
fatty acids in liver , including acetoacetate (30%), βhydroxybutyrate (70%) , acetone
Place produced :
Generated in liver (mitochondria), used
by other tissues
Precursor:
Acetyl-CoA ( from β- oxidation of FA)
Ketone body formation
Thiolase ：
Two acetyl-CoA formed in βoxidation condense with one
another to form acetoacetyl-CoA
by a reversal of the thiolase
HMG-CoA synthase
Condensation of acetoacetyl-CoA
with another molecule of acetylCoA by 3-hydroxy-3methylglutaryl-CoA synthase
forms HMG-CoA
HMG-CoA lyase ：
catalyze the formation of
acetoacetate
β-hydroxybutyrate
dehydrogenase (β-羟丁酸脱氢酶)：
Reduce acetoacetate to form βhydroxybutyrate
Acetoacetate can be
transformed into acetone
Utilization of
ketone bodies
(heart, kidney,
brain, skeletal
muscles)
OH
CH3CHCH2COOH
Succinyl CoA
D(
)
β
羟丁酸
β-hydroxybutyrate
transsulfurase
NAD+
NADH+H+
CoASH+ATP
=
=
PPi+AMP
Succinyl CoA
succinate
CoASH
thiokinase
硫激酶
=
=
O
O
CH3CCH2COH
乙酰乙酸
acetoacetate
O
O
CH3CCH2CSCoA
(乙酰乙酰
CoACoA
)
Acetoacetyl
=
O
2 CH3CSCoA
Acetoacetyl CoA
thiolase
硫解酶
Physiological significance of ketogenesis
1) ketone bodies are normal physiological responses
to carbohydrate shortages, HMG-CoA synthase
only exists in liver, and Succinyl-CoA
transsulfurase exists in extrahepatic tissue.
2)Under starveling condition, ketogenesis is
increased. This allows the heart ,the brain and
skeletal muscles use ketone bodies as energy.
3) The normal concentration of ketone bodies in blood
is very low.﹤0.5mmol/L. Under some pathological
condition (such as diabetes), the synthesis is faster
than utilization, so the concentration of ketone bodies
in the blood is high, (up to 20mmol/L) which is
called as ketonemia ( 酮 血 症 ), and they may be
excreted in the urine, which is called as ketonuria (酮
尿症).
5) Ketone bodies are acidic compounds, the accumulate
of them in the blood will cause ketoacidosis (酮症酸
中毒).
nausea and vomiting of pregnancy, NVP
Summary
Ketone bodies：acetoacetate, β-hydroxybutyrate ,
acetone
Formation and Usage：Formation in liver and usage
in
Liver
extrahepatic
tissue
Extrahepatic
Acetyl-CoA
Acetoacetate
β-hydroxybutyrate
Acetone
tissue
Acetoacetate
β-hydroxybutyrate
Acetone
Acetyl-CoA
The oxidation of glycerol
Entry of glycerol
into the glycolytic
Pathway, Gluconeogenesis
and TG synthesis pathway
Abundant of glycerol
kinase in liver, kidney and
mucous membrane of
small intestine
1. Which two fatty acids are essential fatty acids?
A palmitoleic acid; B oleic acid;
C linoleic acid;
D linolenic acid
Which one is anti-lipolytic hormone?
A glucagon;
B epinephrine;
C norepinephrine; D insulin
Fat metabolism
1. Fat mobilization and hydrolysis
2. Fatty acid β-oxidation
3. Ketone body formation
4. Fat synthesis
Glycerol-phosphate, fatty acid
4. Biosynthesis of triacylglycerols
Location:
All tissues, fat, intestine and liver are
most active tissues.
Material:
glycerol （ glycerol 3-phosphate）
FA (acyl CoA)
(1) The formation of glycerol 3-phosphate
1) In intestine, liver and adipose tissues:
Glycolysis
glucose
dehydrogenase
glycerol 3dihydroxyacetone
phosphate
phosphate
2) In liver and intestine:
glycerol
phosphorylation glycerol 3-phosphate
glycerokinase
(2) FA Biosynthesis
FA synthesis is not the reverse reaction of FA
degradation: by different pathways, different
enzymes, and in different part of cells.
Site: Cytosol of liver, adipose tissue, kidney, brain
and breast.
Materials
Acetyl-CoA provides the first two carbons,
which is elongated by sequential addition of
two-carbon units donated from malonyl-CoA,
NADPH is the reductant. ATP provides energy.
Acetyl CoA (Come mostly from glucose)
NADPH (Pentose phosphate pathway , or
produced by malate enzyme
ATP
Carbonate (HCO3-)
Step1. Transport of the acetyl groups from
the mitochondrion into the cytosol
The acetyl-CoAs are shuttled into the cytosol in the
form of citrate via the citrate transporter of the inner
membrane.
Citric acid transport pathways
Acetyl-CoA is regenerated by the action of ATPdependent citrate lyase in the cytosol.
Oxaloacetate is shuttled back into the mitochondria as
malate (苹果酸) or pyruvate (丙酮酸)
乙酰CoA
Step 2. Malonyl-CoA formation
丙二酰CoA合成
acetyl-CoA
carboxylase
Acetyl-CoA carboxylase
The enzyme has three functional parts: a biotin
carrier protein; an ATP-dependent biotin
carboxylase; and a transcarboxylase
Acetyl-CoA carboxylase catalyzes the two-step
carboxylation reaction of acetyl-CoA on two active sites.
Regulation on acetyl-CoA carboxylase
Acetyl-CoA carboxylase has two forms：inactive dimer
(二聚体）and active polymeric （多聚体）form
Acetyl-CoA carboxylase is regulated by phoshporylation
Glucagon and epinephrine promote phosphorylation
and depolymerization of the enzyme (inactive)
Insulin induces the synthesis and dephosphorylation
of the enzyme (active)
Allosteric regulation :citrate promotes polymerization，
long chain fatty acid promote depolymerization
Step 3. Fatty acid synthesis
Fatty acid synthase complex in mammals
Multienzyme （多功
能酶）polypeptide
complex containing
seven enzyme
activities
250 kDa dimer
ACP:acyl carrier protein, no enzyme activity
KS: β-ketoacyl-ACP synthase酮脂酰合酶
MT:malonyl-transacylase 丙二酰基转移酶
KR: β -ketobutyryl-ACP reductase酮脂酰还原酶
DH: β -hydroxybutyryl-ACP dehydratase脱水酶
ER: enoyl-ACP reductase烯脂酰还原酶
AT: acetyl-CoA-ACP transacetylase乙酰基转移酶
TE: acyl-CoA thioesterase 硫脂酶
ACP: acyl carrier protein
Hydrosulfuryl group
Process of Palmitic Acid synthesis
Acetyl-CoA combines
with –SH group or KS
catalyzed by acetyl β-ketoacyl-ACP synthase
transacylase （转酰基酶）
Malonyl-CoA combines
with the adjacent-SH
group of ACP of the other
monomer （单体）
β-ketoacyl-ACP synthase (KS)
β-酮脂酰ACP合成酶
β-ketobutyryl-ACP
β-酮丁酰ACP
Step 1: condensation
（AT，KS，MT，ACP）
Step 2: β-ketobutyryl-ACP
is reduced to
D- β -hydroxybutyryl-ACP,
using NADPH and the
β -ketoacyl-ACP reductase
(KR)
Step 3: A water molecule
is removed from
b-hydroxybutyryl-ACP
to produce
trans-2-butenoyl-ACP
in a reaction catalyzed
by b-hydroxyacyl-ACP
dehydratase (HD)
脱水酶
Step 4: The carbon-carbon
double bond in
trans-2-butenoyl-ACP is
reduced 丁烯酰
by NAPDH in a reaction
catalyzed
by enoyl-ACP reductase (ER),
producing a saturated acyl on
ACP (butyryl-ACP)
丁酰-ACP
acyl-CoA thioesterase
The overall process of palmitate synthesis
Fatty acids are synthesized by a repeating fourstep reaction sequence
Condensation、Reduction、Dehydration、Reduction
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+ →Palmitate + 7
CO2 + 8 CoA + 14 NADP+ + 6 H2O
Synthesis of polyunsaturated FA
In humans:
There are Δ4、Δ5、Δ8、Δ9 desaturase, can produce
palmitoleic acid (16:1 Δ9) and oleic acid (18:1 Δ9) from
palmitate and stearate
But there are no desaturases in human can produce
double bonds beyond 10 carbon position.
Palmitate is the
Precursor for the
biosynthesis of
other fatty acids
5. Process for synthesis of TG:
Monoacylglycerol (MG) pathway
(intestine)
Diacylglycerol (DG) pathway
(liver, adipose)
（1） monoacylglycerol pathway
(In intestine)
①
Acyl CoA synthetase
CoA-SH + RCOOH
ATP
AMP PPi
RCOCoA
H2O
②
=
monoacylglycerol
CoA
=
R2COCoA
O
CH2O-C-R2
Acyl CoA
O
transferase
CHO-C-R1
O
R3COCoA
CoA CH2O-C-R3
=
Acyl CoA
transferase
=
CH2OH
=
=
CH2OH
O
CHO-C-R1
O
CH2O-C-R2
O
CHO-C-R1
CH2OH
1,2-diacylglycerol
triacylglycerol
(2) Diacylglycerol pathway：liver , adipose
O
CH2O-C-R1
=
CH2OH
Acyl CoA
transferase
CHOH
CH2O- Pi
Glycerol
3 - 磷酸甘油
3-phosphate
R1COCoA
CHOH
CoA
CH2O- Pi
R2COCoA
=
Pi
O
CH2O-C-R3
=
Phosphatidate
磷脂酸
磷脂酸
=
CH2O- Pi
Acyl CoA
transferase
O
CHO-C-R2
=
=
O
CH2O-C-R1
O
CHO-C-R2
=
=
O
CH2O-C-R1
phosphatidase
CoA
溶血磷脂
Lysophosphatidate
1-酯酰-3 - 磷酸甘油
O
CH2O-C-R1
O
CHO-C-R2
Acyl CoA
transferase
CH2OH
R3COCoA
1，2-甘油二酯
Diacylglycerol
Materials：acyl-CoA and
provided by glucose
CoA
甘油三酯
Triacylglycerol
glycerol 3-phosphate,
Regulation of triacylglycerol metabolism
Hormone-sensitive triglyceride lipase
Carnitine acyltransferase Ⅰ
Acetyl CoA carboxylase (ACC)
Section 3. Metabolism of Phospholipid
Phospholipids (PL)
lipoid
cholesterol and cholesteryl ester
glycolipids
Concept of Phospholipid:
A group of lipids containing phosphate present in all cells as
well as in the plasma.
Classification:
glycerophospholipid→having glycerol
甘
油
鞘
氨
醇
FA
FA
Pi
X
sphingosine
glycerol
Sphingolipids → having sphingosine
FA
Pi
X
1.The metabolism of glycerophospholipid
Structure:
O
O
CH2O-C-R1
R2C-O-CH
O
CH2O-P-OX
Substitute
group
OH
function:
The basic structure of biomembrane
Major classifications of glycerophospholipid
choline
Phosphatidylcholine (PC)
lecithin
Phosphatidylethanolamine (PE)
cephaline
serine
Phosphatidylserine (PS)
ethanolamine
inositol
Phosphatidylinositol (PI)
Phosphatidylglycerol (PG)
Glycerol
Diphosphatidylglycerol (DPG)
Cardiolipin
乙脑—磷脂酰乙醇胺 （脑磷脂）
二心—二磷脂酰甘油 （心磷脂）
暖壶的胆—磷脂酰胆碱 （卵磷
2. Metabolism of Phospholipid
Synthesis of glycerophospholipids
Degradation of glycerophospholipids
(1) Synthesis of glycerophospholipids
① synthesis site:
Tissue: all tissue of body, most active
places are liver, kidney.
Cell site: endoplasmic reticulum (ER)
② Precursor and cofactor ：
glycerol
a. FA : From carbohydrate (glucose metabolism)
poly unsaturated fatty acid from plant oil
b. Glycerol: From TG degraded
c. Choline, ethanolamine, Serine, Inositols
e. ATP, CTP
甘
油
FA
FA
Pi
X
③ process of synthesis
A. Diacylglycerol (DAG ) -pathway
for lecithin and Cephalin
（卵磷脂与脑磷脂)
glucose
Glycerol-3-phosphate
Phosphotidic acid
Diacylglycerol
serine
CDPethanolamine
Phosphatedyl
ethanolamine
Cephalin
CDP-choline
Phosphatedyl
choline
lecithin
Acyl-CoA
triacylglycerol
CO2
Serine
HOCH2-CH-COOH
NH2
ethanolamine
Choline
+CH3
HOCH2CH2N+(CH3)3
HOCH2CH2NH2
ATP
ATP
ADP
ADP
P OCH2CH2N+(CH3)3
P OCH2CH2NH2
CTP
CTP
PPi
PPi
CDP-OCH2CH2NH2
CDP-OCH2CH2N+(CH3)3
DG
Cephalin
lecithin
B. CDP-DAG pathway
O
O
CH2O-C-R1
R2C-O-CH
O
Glucose
Glycerol-3-phosphate
2 acyl-CoA
CH2O-P-OX
OH
OH
Phosphotidic acid
CTP
CDP-diacylglycerol
Serine
Phosphatedyl
serine
磷脂酰丝氨酸
Inositol
Phosphatedyl
inositol
磷脂酰丝氨酸
Phosphatedyl
Acyl-CoA
glycerol
Diphosphatedyl
glycerol
Cardiolipin
(2). Degradation of glycerophospholipid
Enzyme: phospholipase (磷脂酶, PLA)
including A1,A2,B1,B2,C,D.
溶血磷脂II
Lysophospholipid II
O
PLA1
CH2OH
R2C-O-CH
O
O
CH2O-P-O—X
CH2O-C-R1
R2C-O-CH
PLD
PLB2
OH
O
PLB1
CH2O-P-O—X
PLA2
O
OH
PLC
溶血磷脂 I
O
CH2O-C-R1
HO-CH
O
CH2O-P-O—X
Lysophospholipid I
Lysophospholipid can cause hemolysis (溶血）。
1. Some snake venom contain phospholipase A1 or A2.
Bited by these snakes, may suffer from hemolysis,
shock(BP), even renal failure
2. Pancreatitis
:
Some reasons to activate phospholipaseA2 (existed in
most cells) cause Pancreatitis.
Dipalmitoyl phosphatidylcholine
Lung surfactant , which is
synthesized shortly before
parturition in full-term
infants. Deficiency of lung
surfactant in the lungs of
many preterm newborns gives
rise to respiratory distress
syndrome
Sphingolipids
sphingosine
鞘
氨
醇
X---- Choline
Ethanolamine
FA
Pi
X
ceramide
X = Choline、Ethanolamine、
Multiple sclerosis
Multiple sclerosis which is a demyelinating disease, there
is loss of both phospholipids (particularly ethanolamine
plasmalogen) and of sphingolipids from white matter,
Thus, the lipid composition of white matter resembles
that of gray matter.
Healthy neuron
Partly demyelinated
Injured
neurofilament
Section 4. Cholesterol metabolism
Cholesterol : A solid compound contains hydroxy
group, which is firstly isolated from animal
Cholelithiasis.
Cholesteryl ester : combined with long-chain fatty
acid
Plants and fungus do not
contain cholesterol, but have
sitosterol (谷固醇), ergosterol
(麦角固醇)
Bacteria do not contain
sterol material
* Structure of cholesterol：
Derivant of cyclo-pentano-phenanthrene ring
环戊烷多氢菲
12
13
11
1
C
H
H
10
9
2
H
B
A
3
4
5
6
H
8
7
17
16
D
14
H
15
Cholesterol in animals：(27C)
O
Cholesteryl ester
C
R
O
β-sitosterol
(谷固醇)
Plant sterol：(29C)
β -ergosterol
(麦角固醇)
Yeast：(28C)
* Functions of cholesterol：
(1) Essential component of biomembrane
(2) Transform into many kinds of physical active
materials. Such as, bile acid, VitD3 , steroid hormone.
( progesterone, testosterone and cortisol)
(睾丸激素)
(3) Component of plasma lipoprotein.
* Content and distribution in body.
Content： about 140g
Distribution: appear in most of tissue.
a)about ¼ in brain and nerve tissue.
b)Adrenal gland and ovary organ are high
c)A little bit high in liver, kidney, intestines, skin, fat
tissue.
d)Distributing low in muscle.
The existed form: Free cholesterol
Cholesteryl ester
1. Synthesis of cholesterol
Place :
All tissue except brain and mature red blood cells.
more active in liver ( 80%), intestine, cortex of
adrenal, sexual gland.
Location:
In cytosol and endoplasmic reticulum
Materials:
1) 18×acetyl CoA (the only carbon source)
from glucose aerobic oxidation
2) 16 ×NADPH(H+)
from pentose phosphate pathway (provide H)
3) 36×ATP (provide energy)
甲羟戊酸
mevalonate
HMG-CoA
HMG-CoA
reductase
Isopentenyl pyrophosphate
二甲丙烯焦磷酸
焦磷酸法尼酯
squalene
cholesterol
27C
羊毛固醇
30C
鲨烯
The process: has four major steps
1). Acetyl-CoAs are converted to 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA)
2). HMG-CoA is converted to mevalonate (甲羟戊酸)
3). Mevalonate is converted to squalene (鲨烯)
4). Squalene is converted to cholesterol.
2. Regulation of cholesterol synthesis
key enzyme : HMGCoA reductase
1) Fasting and food full （饥饿和饱食）
a. fasting enzyme activity↓ cholesterol↓
as materials is shortage
b. food full  enzyme activity↑  cholesterol↑
2) Cholesterol
cholesterol↑  enzyme activity↓(feedback )
3) Hormone
1) Insulin  HMG reductase synthesis↑  Cholesterol↑
2) Glucagons, Adrenal cortical hormone  HMG
reductase synthesis↓  Cholesterol ↓
HMGCoA reductase
3) Thyroxine  HMGCoA reductase ↑  Cholesterol ↑
thyroxine  Cholesterol converted to bild acid ↑ 
Cholesterol ↓↓
4) Cycle rhythm （周期节律）
in midnight  Enzyme activity↑↑  synthesis ↑↑
noon  as Enzyme activity↓↓  synthesis ↓↓
The de novo synthesis of
cholesterol is regulated
to complement the
dietary uptake
X represents unidentified
metabolites of cholesterol
that stimulate proteolysis
of HMG-CoA reductase.
HMG-CoA
Digestion and absorption of Cholesterol
We need about 1g cholesterol every day and most of
it is synthesized by our bodies
The free cholesterol in food can be absorbed directly,
and cholesteryl ester can be digested by cholesteryl
esterase and then be absorbed (消化吸收).
Most of cholesterol in food can not be absorbed
Our bodies seldom absorb plant sterols （植物固醇）
and the latter disturb the normal absorption of
cholesterol
Synthesis of cholesteryl esters
In cell：
Acyl-CoA cholesterol acyltransferase, ACAT
Acyl-CoA + Cholesterol
Cholesteryl ester + CoA
In plasma：
Lecithin cholesterol acyltransferase, LCAT
Phosphatidylcholine +
Cholesterol
Cholesteryl ester +
lysophosphatidylcholine
Transformation of cholesterol
Cholesterol can not be totally metabolized， it
transforms into many kinds of physical active
materials, such as, bile acid, VitD3, steroid
hormone
steroid hormones:
 progesterone,
testosterone,
cortisol, estradiol,
aldosterone
Case III
Hypercholestrolemia
The serum cholesterol is correlated with the
incidence of atherosclerosis and coronary heart
disease
Hereditary factors, dietary and environmental
factors influence serum cholesterol concentration
Polyunsaturated fatty acids (Fish oil ) reduce serum
cholesterol concentration
HMG-CoA reductase inhibitor
(lovastatin)
Sitosterol
inhibits cholesterol absorbtion
Section 5. the metabolism of plasma
lipoprotein
1. Blood lipid
Concept: all the lipids contained in plasma, including
TAG, phosphalipids, cholesterol and their ester, FA.
Lipoprotein: The form of blood lipid exist and transport.
protein£¨ apolipoprotein£¬Apo£©
TAG
Cholesterol and their ester
phospholipid
Lipoproteins are globular, micelle-like particles
consisting of a hydrophobic core of triacylglycerols
and cholesterol esters surrounded by an amphipathic
coat of protein, phospholipid and cholesterol.
2. Type and component of plasma lipoprotein
Classification
（1）Electrophoresis : according to the velocity
- Lipoprotein
pre b-Lipoprotein
b-Lipoprotein
CM (chylomicron)

slow
CM
b preb

♁
fast
(2) Ultra centrifugation：according to the density
Low
CM (chylomicron )
VLDL (pre-β- lipoprotein)
LDL (β- lipoprotein )
HDL (α-lipoprotein)
High
rotor
Lipoproteins observed under electron microscope
Characteristics of the four classes of lipoproteins
CM
density
lipid
protein
content
Apoprotei
ns
载脂
蛋白
＜0.95
TG richest
80~90%
VLDL
LDL
HDL
0.95~1.006 1.006~1.063 1.063~1.210
TG rich
Ch and CE PL 50%
40~50%
50~70%
Poorest 1% 5~10%
20~25%
apoB48、E apoB100、 apoB100
AⅠ、AⅡ
CⅠ、CⅡ
AⅣ、CⅠ
CⅢ、 E
CⅡ、CⅢ
rich，
about 50%
apo AⅠ、
AⅡ
Apolipoprotein, apo
Concept:
The protein in the plasma lipoprotein
Category（have 5 classes and 18 subunit）
apo A: AⅠ、AⅡ、AⅣ
apo B: B100、B48
apo C: CⅠ、CⅡ、CⅢ
apo D
apo E
Function:
① Combination and transport of lipids
② Recognizing the lipoprotein receptors
AⅠ recognizing HDL receptor
B100，E recognizing LDL receptor
③ Regulating key enzymes of lipoprotein metabolism
apo A I activate LCAT
apo C II activate lipoprotein lipase（LPL）
apo A II activate hepatic lipase（HL）
apo CⅢ inhibit LPL
3. Metabolism of plasm lipoprotein
 Enzymes：
Lipoprotein lipase (LPL)：Synthesized in all tissue and
locates at the membrane surface of microvascular
endothelium , it can hydrolyze TG in CM and VLDL，
ApoC-II can activate this enzyme
Hepatic lipase (肝脂肪酶, HL)：Synthesized in liver and
locates at surface of liver cells, it can digest the TG in
remnants of CM and VLDL
Lecithin cholesterol acyltransferase (LCAT)：Synthesized
in liver and secreted into blood, it act on free cholesterol on
surface of HDL and drive cholesterol into the core of HDL,
ApoA-I is its activator
1). Metabolism of CM
小肠上皮
血管内皮
乳糜微粒残粒
2). Metabolism of VLDL and LDL
3). Metabolism of LDL
Liver
receptor
①
modified LDL
②
①
Other tissue
LDL receptor
scavenger
receptor
macrophage
/endothelial cell
4). Metabolism of HDL
LDL受体
scavenger receptor class B type I
Site and function of the four classes of lipoproteins
sorts
CM
VLDL
LDL
HDL
Produce
site
intestine
liver cell
VLDL
transform in
blood
Liver,intestine
function
transport
exogenous
TG and Ch
from
intestine to
liver
transport
endogenous
TG
produced in
liver and
metabolized
into LDL
transport
endogenous
ChE
produced in
liver to other
tissues.
transport ChE
from
extrahepatic
tissues to liver.
1. Which of the plasma lipoproteins is best described as
follows: synthesized in the liver, containing a high
concentration of triacylglycerol and mainly cleared from
the circulation by adipose tissue and muscle?
A. Chylomicrons; B. High-density lipoprotein;
C.Intermediate density lipoprotein; D. Low-density
lipoprotein; E. Very low-density lipoprotein
2. The subcellular site of the synthesis of
cholesterol is:
A.The cytosol and the endoplasmic reticulum
B.The matrix of the mitochondria
C.The mitochondrial intermembrane space
D.The Golgi apparatus