chapter 5 metabolism of lipids

The biochemistry and molecular biology department of CMU

Chapter 5

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 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 aci

ds are called essential fatty acids, bec

ause they cannot be synthesized by th

e 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

O

HO

O

O C

O

R1

C

O

R3

1

2

3

Overview of triglycerides metabolism

Triglycerides(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 adi

pocytes 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

CH2OH

CHO H

CH2OHglycerolkinase

CH2OH

CHO H

CH2O PGlycerol L-Glycerol

3-phosphate

ATPADP

CH2OH

CO

CH2O PDihydroxyacetone

phosphate

D-Glyceraldehyde 3-phosphate

Glycolysis

NAD+

NADH+H+

CHO

CH

CH2O 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+

C

R

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 O

FADH2

FAD

Fatty 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

OO

NADH + 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 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

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

O

S CoA

2 Acetyl-CoA

CH2 C

O

S CoAC

O

CH3

CH2 C

O

S CoAC

OH

CH2

CH3

OOC

¦Â-Hydroxy-¦Â-methylglutaryl-CoA¡¡ ¡¡ ¡¡ ¡¡ £¨HMG-CoA£©

Acetoacetate

HMG-CoAlyase

C CH3

O

CH3

HSCoA

CH CH2

OH

CH3 COO

CH2 COOC

O

CH3

CH3 C

O

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

H3C

C-S-CoAO

9

H3C18

1

stearic acid (C18:0) stearoylCoA

H3C

C-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

NADPH

malate

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

SCoA

acetyl-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

Fu

nctio

nal

divisio

n

Subunitdivision

ACP contains 4’-phosphopantotheine.

ATMT

KS① condensation

②

KR

③ dehydration

④

HD

ER

AT

TE

NADPH + H+

NADP+

(CH2)14 C O

O

CH3

NADP+

+ H+NADPH

CH3 C S

O

CH3 C S

O

OOC CH2 C S

O

C CH2 C S

O

O

CH3

CH CH2 C S

O

OH

CH3

CH CH C S

O

CH3

CH2 CH2 C S

O

CH3

KS-HSACP-HS

CH2 CH2 C S

O

CH3CO 2

H2O

H2O

OOC CH2 C S CoA

O

CH3 C S

O

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

O

HO

OH

OH CH2

C

CH2

CR2

O

HO

OH

O C

O

R1

HSCoAacyl CoA

acyl CoA transferase

CH2

C

CH2

CR2

O

HO

O

O C

O

R1

C

O

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

Growth

ADP

ATP

fatty acids & triacyl-gl

cerolsObesity

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 acids

nitrogenous 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 & kidney

Endoplasmic reticulum

Pathways:

CDP-diacylglycerol pathway

Diacylglycerol pathway

a. FA Glycerol

b. 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

P

Phosphocholine

CDP-ethanolamineO CH2 CH2 NH2 O CH2 CH2 N(CH3)3CDP

CDP-choline

Phosphatidylethanolamine

Phosphatidylcholine

3 SAMPhosphatidylserine

CDP-Diacylglycerol pathway

PhosphotidateCTP

PPi

CDP-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 15

1617

18

19

20

2122 23 24 25

26

27

Cholesterol ester

OCR

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.

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

acidsConjugated bile acids

Primary bile acids

Cholic acidGlycocholic aci

dTaurocholic 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

freeTG

cholesterol

phospholipidslecithinsphingolipidscephalin

ester

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

－ ＋

Origin CM

LDL VLDL HDL

Pre-

CM

Separation of plasma lipoproteins by electrophoresis on agarose gel

§ 5.3 Structure

§ 5.4 Composition of lipoprotein

CM VLDL LDL HDL

Density(g/ml) <1.0060.95-1.006

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 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.

Cholesterol phospholipids

Triacylglycerols andcholesteryl esters

Apolipoproteins structure of CM

Metabolic fate of CM

summary of CM• Site of formation: intestinal mucosal cel

ls

• 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 lipids

Ⅰ CM TAG↑ ↑ ↑ CH↑

Ⅱa LDL CH↑ ↑

Ⅱb LDL, VLDL CH↑ ↑ TAG↑ ↑

Ⅲ IDL CH↑ ↑ TAG↑ ↑

Ⅳ VLDL TAG↑ ↑

Ⅴ VLDL, CM TAG↑ ↑ ↑ CH↑