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biochemistry and molecular biology department
Metabolism of Lipids
• Lipids are substances that are insoluble or immiscible in water, but soluble in organic solvents.
Concept
Lipids
Lipoids
Fats (Triglyceride or triacylglycerole)
To store and supply energy
Phospholipids Glycolipids Cholesterol Cholesterol ester
To be important membrane components
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
Contents
Section 1 Fatty acids
§1.1 Classification of fatty acidsNumerical 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
CH2
C
CH2
CR2
OHO
O
O C
O
R1
C
O
R3
1
2
3
Overview of triglycerides metabolismTriglycerides
(fats)
Fatty acids
Acetyl-CoA
Esterification Lipolysis
Lipogenesis ¦Â-Oxidation
Diet
CarbohydrateAmino acids
2CO2
TAC
Cholesterolo-genesis
Cholesterol
Steroids
Steroido-genesis
Ketogenesis Ketone bodies
§ 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 metabolismPlace: liver, kidney, intestine
CH2OHCHO HCH2OH
glycerolkinase
CH2OHCHO HCH2O P
Glycerol L-Glycerol 3-phosphate
ATP ADP
CH2OHCOCH2O P
Dihydroxyacetone phosphate
D-Glyceraldehyde 3-phosphate
Glycolysis
NAD+
NADH+H+
CHOCHCH2O P
OH triose phosphateisomerase
glycerol 3-phosphatedehydrogenase
Glyconeogenesis
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.
+ HSCoAacyl-CoA
synthetase
Mg2+ATP AMP + PPi
R CO
O
Fatty acid
R CO
S CoA acyl-CoA
Key points of FA activation
1. Irreversible
2. Consume 2 ~P
3. Site: cytosol
Stage 2Transport of acyl CoA into the
mitochondria ( rate-limiting step)
• Carrier: carnitine
Rate-limiting enzyme• carnitine acyltransferase Ⅰ
H3C N CH2 CH CH2
CH3
CH3
OH
COO+R
C
SCoA
O
H3C N CH2 CH CH2
CH3
CH3
O
COO+
CR
O
Carnitine
Fatty acyl carnitine
HSCoA
carnitine acyltransferase ¢ñ
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 (CH2)n C C C SCoA
H
H
H
H O
H3C (CH2)n C C C SCoA
H
H OFADH2
FADFatty acyl-CoA
acyl-CoA dehydrogenase
trans-¦¤2-enoyl-CoA
Step 2. Hydration
H3C (CH2)n C C C SCoA
H
H O
H3C (CH2)n C C C SCoA
H
O
H2O
OH
Trans-¦¤2-enoyl-CoA
H
H 3-L-Hydroxyacyl-CoA
enoyl-CoA Hydratase
Step 3. Dehydrogenate
H3C (CH2)n C C C SCoA
H
OOH
H3C (CH2)n C CH2 C SCoA
OONADH + H+
NAD+
H
H 3-L-Hydroxyacyl-CoA
hydroxyacyl-CoAdehydrogenase
β -Ketoacyl-CoA
Step 4. Thiolytic cleavage
H3C (CH2)n C CH2 C SCoA
OO
CH3 C SCoA
O
H3C (CH2)n C SCoA +
O
HSCoAβ -Ketoacyl-CoA
Acetyl-CoAFatty acyl-CoA(2C shorter)
β -Ketothiolase
β- oxidation of fatty acids
The β-oxidation pathway is cyclic
one cycle of the β-oxidation:
fatty acyl-CoA + FAD + NAD+ + HS-CoA →fatty acyl-CoA (2 C less) + FADH2 +
NADH + H+ + acetyl-CoA
Summary
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.
The net ATP production: 131 － 2 = 129
Energy yield from one molecule of palmitic acid
TAC
palmitoyl-CoA 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+
-2 ~P respiratory chain
palmitic acid
activation
7 turns of ¦Â-oxidation
8¡Á12
7¡Á2
respiratory chain
7¡Á3
§ 2.1.3 Other Oxidations of Fatty acids
1. Oxidation of unsaturated fatty acids2. Peroxisomal fatty acid oxidation3. 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
Acyl-CoA oxidase
shorter chain fatty acids
β-oxidation
FAD
3. Oxidation of propionyl-CoA
propionyl-CoA
Carboxylase (biotin)EpimeraseMutase (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, β-hydroxybutyrate, and acetone.
The formation of ketone bodies (Ketogenesis)
Location: hepatic mitochondria
Material: acetyl CoA
Rate-limiting enzyme: HMG-CoA synthase
thiolase
HSCoAHMG-CoA synthase
NAD+
NADH+H+
¦Â-Hydroxy-butyrate
CO2Acetone
Acetoacetyl-CoACH3 C
OS CoA2 Acetyl-CoA
CH2 CO
S CoACO
CH3
CH2 CO
S CoACOH
CH2
CH3
OOC
¦Â-Hydroxy-¦Â-methylglutaryl-CoA¡¡ ¡¡ ¡¡ ¡¡ £¨HMG-CoA£©
Acetoacetate
HMG-CoAlyase
C CH3
OCH3
HSCoA
CH CH2
OHCH3 COO
CH2 COOCO
CH3
CH3 CO
S CoA+
Acetyl-CoA
¦Â-hydroxybutyrate dehydrogenase Acetyl-CoA
Utilization of ketone bodies (ketolysis) at extrahepatic tissues
Succinyl-CoA transsulfurase
HSCoAATP
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.
Glucose Glucose exported as fuel for tissues such as brain
oxaloacetate
Fattyacids Acetyl-CoA
β-oxidation
gluconeogenesis
CitricAcid cycle
Ketone bodiesexported as energy source for heart, skeletal muscle, kidney, and brain
Ketone body formation
Hepatocyte
Acetoacetate, β-hydroxybutyrate,
acetone
CoA
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
oleic acid (C18:1 9)
oleoylCoA
palmitic acid (C16:0) palmitoylCoA
H3CC-S-CoAO
9
H3C18
1
stearic acid (C18:0) stearoylCoA
H3CC-S-CoAO
C-S-CoAO
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
citrate
oxaloacetate
pyruvate
NADH
NADPHmalate
cytosolmitochondrion
CO2
malate
oxaloacetate
citrate
pyruvate
Acetyl CoA Acetyl CoA
glucose
TCAC
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
Malonyl-CoA serves as the donor of two-carbon unit.
CH3 C
O
SCoAacetyl-CoA
+ HCO3acetyl-CoAcarboxylase
ATP ADP + Pibiotin
OOC CH2 C SCoA
O
malonyl-CoA
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.
acetyl-CoA + HCO3 + H+
acetyl-CoA carboxylase (biotin)
malonyl-CoA
long chain acyl-CoA
ATP ADP + Pi
glucagon insulin
citrateisocitrate
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.
(2) Repetitive steps catalyzed by fatty acid synthase
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)
Cys
HS
PhP
HS
AT
KS
MTHD ER KR
ACP
TE
Cys
HS
PhP
HS
AT
KS
MTHDERKR
ACP
TE
Functionaldivision
Subunitdivision
ACP contains 4’-phosphopantotheine.
ATMT
KS① condensation
②
KR
③ dehydration
④
HD
ER
AT
TE
NADPH + H+
NADP+
(CH2)14 C OO
CH3
NADP+
+ H+NADPH
CH3 C SO
CH3 C SO
OOC CH2 C SO
C CH2 C SO
OCH3
CH CH2 C SO
OHCH3
CH CH C SO
CH3
CH2 CH2 C SO
CH3
KS-HSACP-HS
CH2 CH2 C SO
CH3CO 2
H2O
H2O
OOC CH2 C S CoAO
CH3 C SO
CoA
HS CoA
HS
reduction
(After 7 rounds)
HS CoA
HS
HS
HS
HS
HS
HSHS
reduction
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+
palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O
The overall reaction of synthesis:
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 as acetyl CoA
2 carbon units added, as 3 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
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
CH2
C
CH2
HSCoAacyl CoA
acyl CoA transferase
2-monoacylglycerol 1,2-diacylglycerol
triacylglycerol
CR2
OHO
OH
OH CH2
C
CH2
CR2
OHO
OH
O C
O
R1
HSCoAacyl CoA
acyl CoA transferase
CH2
C
CH2
CR2
OHO
O
O C
O
R1
CO
R3
2. Diacylglycerol pathway
glycolysis
Summary• Places: small intestine, liver, adipose
tissue
• 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
adipose tissue
Heat
Work or
GrowthADP
ATP
fatty acids & triacyl-glcerols
Obesity
CO2 + H2O
Food
Section 3 Metabolism of Phospholipids
• Phospholipid refers to phosphorous-containing lipids.
Phospholipids
Glycerophospholipids
Sphingolipids
§ 3.1 Classification and Structure of Glycerophospholipids
• Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base.
Phosphatidylcholine
fatty acidsnitrogenous base
glycerol
CH2 O
C H
CH2
O
O
C
C
P
R1
R2
O
O
O
O
OH
X
甘油
脂酰基
脂酰基
含氮化合物
The basic structure of glycerophospholipid
glycerolfatty acyl group
Nitrogenous basefatty acyl group
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 &
kidneyEndoplasmic reticulum
Pathways:CDP-diacylglycerol pathwayDiacylglycerol pathway
a. FA Glycerolb. poly unsaturated fatty acid from plant oil c. choline ethanolamine serine inositol
d. ATP, CTP
e. Enzymes and cofactors
The system of synthesis
from carbohydrate
from food or synthesis in body
Diacylglycerol pathway
SerineEthanolamine
CO2
ATP
ADP
CTP
PPi
DG
CMPCO2
ATP
ADP
CTP
PPi
DG
CMP
3 SAMHO CH2 CH
NH2
COOH HO CH2 CH2 NH2 HO CH2 CH2 N(CH3)3
Choline
PhosphoethanolamineO CH2 CH2 NH2P O CH2 CH2 N(CH3)3
CDP
PPhosphocholine
CDP-ethanolamineO CH2 CH2 NH2 O CH2 CH2 N(CH3)3CDP
CDP-choline
Phosphatidylethanolamine
Phosphatidylcholine
3 SAMPhosphatidylserine
CDP-Diacylglycerol pathway
PhosphotidateCTP
PPiCDP-diacylglycerol
CMP
CMP
CMP
Glycerol 3-phosphate
G
Phosphatidyl serinePhosphatidyl inositol
Phosphatidyl glycerol
Diphosphatidyl glycerol(cardiolipin)
SerineInositol
Dihydroxyacetonephosphate
Phosphatidylethanolamine (Cephalin)
Phosphatidylcholine (Lecithin)
Phosphatidylserine
CDP-diacylglycerol
Diphosphatidyl glycerol (Cardiolipin)
Phosphatidylglycerol
Phosphatidylinositol
§ 3.3 Degradation of glycerophospholipids by
phospholipase
CH2 O
C H
CH2
O
O
C
C
P
R1
R2
O
O
O
O
OH
X
A2
A1
C
D
CH2 O
C H
CH2
HO
O
C
P
R1
O
O
O
OH
X
B1
CH2 OH
C H
CH2
O
O
C
P
R2
O
O
O
OH
XB2
Lysophospholipid-1 Lysophospholipid-2
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.
CH2
C HO
CH2O
O C R1
O
P O
O
O
X
H2O
CR2
OOCR2
O
CH2
C HHO
CH2O
O C R1
O
P O
O
O
X
Lysophospholipidphospholipid
PLA2
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.
CH3
CH3
HO
H3C CH3
CH3
A B
C D
12
34
56
7
89
10
1112
13
14 1516
17
18
19
20
2122 23 24 25 26
27
Cholesterol ester
OCR
O
§ 4.2 Synthesis of cholesterolLocation:• 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.
HMG CoA reductase is the rate-limiting enzyme
Acetoacetyl-CoA
Acetyl-CoAHMG-CoA
The total process of cholesterol de novo synthesis
Regulation of cholesterol synthesis
MVAHMG CoA reductase
cholesterol
bile acid
fasting Glucagon
after meal insulin thyroxine
HMG CoA
§ 4.3 Transformation and excretion of cholesterol
Steroidhormones
Bile acids
Cholesterol
Vitamin D
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 Conjugated bile acids
Primary bile acids
Cholic acid Glycocholic acid Taurocholic acid
Chenodeoxy-cholic acid
Glycocheno-deoxycholic
acid
Taurocheno-deoxycholic acid
Secondary bile acids
Deoxycholic acid
Glycodeoxy-cholic acid
Taurodeoxy-cholic acid
Lithocholic acid
Glycolitho-cholic acid
Taurolitho-cholic acid
(2) Strcture of bile acids
HO OH
OH
H
COOH
HO OH
OH
H
CONHCH2COOH
HO OHH
COOH
HO OH
OH
H
CONHCH2CH2SO3H
cholic acid chenodeoxycholic acid
glycocholic acid taurocholic acid
3 7
12
HO
OH
H
COOH
HO H
COOH
deoxycholic acid 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 (glucocorti-coid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol
Steroids derived from cholesterol
3. Conversion into 7-dehydrocholesterol
cholesterol
(mitochondria in the kidney)
1¦Á-hydroxylase
7-dehydro-cholesterol
ultraviolet light
cholecalciferol (VD3)
25-hydroxylase
(microsome in the liver)
1,25-(OH)2-D3
£¨ in skin£©
£¨ active Vit D3£©25-OH-D3
§ 4.4 Esterification of cholesterol
• in cells
HO OCR
O
cholesterol cholesteryl ester
acyl CoA cholesterol
acyl transferase(ACAT)
acyl CoASHCoA
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.
blood lipids
freeTGcholesterol
phospholipidslecithinsphingolipidscephalin
ester
FFA
§ 5.2 Classification of plasma lipoproteins
1. electrophoresis method:
- Lipoprotein fastpre -Lipoprotein-LipoproteinCM (chylomicron) slow
2. Ultra centrifugation method：high density lipoprotein (HDL) highlow density lipoprotein ( LDL)very low density lipoprotein ( VLDL) CM (chylomicron ) low
electron microscope
－ ＋
Origin CM
LDL VLDL HDL
Pre-
CM
Separation of plasma lipoproteins by electrophoresis on agarose gel
§ 5.3 Structure
§ 5.4 Composition of lipoproteinCM VLDL LDL HDL
Density(g/ml) <1.006 0.95-1.006
1.006-1.063
1.063-1.210
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
§ 5.5 Apolipoproteins
Functions of apolipoproteinsa . 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.
Cholesterol phospholipids
Triacylglycerols andcholesteryl esters
Apolipoproteins structure of CM
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.
Metabolic fate of VLDL and production of LDL
Nascent VLDL
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.
Internalization Lysosomal hydrolysisLDL binding
LDL receptors
Cholesterolester
protein
LDL
Cholesterol
Cholesteryloleate
Amino acids
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 re-esterification 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” .
VLDL LDL
HDL
Cholesterol
HeartLiver
“BAD” Deposit
Excretion “Good”
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 lipidsⅠ CM TAG↑ ↑ ↑ CH↑Ⅱa LDL CH↑ ↑Ⅱb LDL, VLDL CH↑ ↑ TAG↑ ↑Ⅲ IDL CH↑ ↑ TAG↑ ↑Ⅳ VLDL TAG↑ ↑Ⅴ VLDL, CM TAG↑ ↑ ↑ CH↑
