Lipid Metabolism.ppt

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الِقرأَن فى الحيوية للكيمياَء الرئيَسية االًقَساٍمالكريم

3

Lipid Metabolism

By Dr. Gamil Abdalla

4

Course outlines

1. Lipid digestion and absorption and their errors

2. Fate of absorbed lipids

3. Lipolysis and Lipogenesis

4. Fatty acid oxidation and synthesis

5. Ketogenesis and ketolysis

6. Cholesterol and Lipiprotein metabolis

7. Fatty liver

5

6

• Lipid family– Triglycerides (fats & oils)– Phospholipids– Sterols (cholesterol)– cholesterol esters are digested by esterase

to fatty acids and cholesterol which absorbed as such

7

Importance of lipids

• As storage and transport form of metabolic fuel

• To keep the body temperature

• Source for essential FA and oil soluble vitamins

• To protect important organs

8

Lipid Digestion

• Challenges– Lipids are not water soluble– Triglycerides too large to be absorbed

• Digestive solution– Triglycerides mix with bile and pancreatic

secretions• Emulsification and digestion

9

Digestion of Triglycerides

• Minor digestion of triacylglycerols in

1. Mouth by lingual lipase

2. Stomach by gastric lipase (in infants only).

• Major digestion of all lipids in the lumen of

the duodenum/ jejunum by Pancreatic lipases

10

Bile

• Produced in liver, stored in gallbladder

• Alkaline solution composed of:– Bile salts– Cholesterol– Lecithin– Bilirubin

• Responsible for fat emulsification

11Mixed micelle formed by bile salts, triacylglycerols and pancreatic lipase.

12

Digestion of TG

• Bile salts emulsify lipids

• Pancreatic lipase acts on triglycerides– Triglycerides 2 monoglyceride + 2

fatty acids

• Pancreatic colipase– Activated by trypsin– Interacts with triglyceride and pancreatic lipase

• Improves activity of pancreatic lipase

13

Pancreatic Colipase

• Secreted from pancreas as procolipase– Activated (cleaved) by trypsin

• Anchors lipase to the micelle– One colipase to one lipase(i.e., 1:1 ratio)

14

Dietary Fat(large TG droplet)

Bile Salts

Lipid emulsion

Lipase 2-Monoglyceride

+ 2 FFA

Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli

15

Emulsification

• Produces small lipid spheres– Greater surface area

• Lipases attack TG at 1 and 3 positions

Glycerol

Fatty Acid1

Fatty Acid2

Fatty Acid3

Lipase

Glycerol

Fatty Acid3

Fatty Acid1Fatty

Acid2

Triglyceride 2-Monoglyceride

+

2 Free Fatty Acids

2 H20

16

12

3 4

17

Digestion of phospholipids

PLA2

PLA1

PLcPLD

18

Intestinal Wall

Liver GlycerolPortal circulation

Short chain FA

Lumin

Glycerol

Short chain FA

Triacylglycerols

Chylomicrones

Protein

SystimicCirculation

Th

oracicD

uct

Bile salts

Monoacylglycerol

Long chain FA

Cholesterol

Phospholipids

+

+

+

+

Bile salts

Monoacylglycerol

Long chain FA

Cholesterol

PhospholipidsLacteal

Lipid AbsorptionLipid Absorption

19

• Pancreatic insufficiency (chronic pancreatitis and cystic fibrosis)

• Acidity of duodenal content (zollinger-Ellison syndrome)

• Deficiency of bile salts (ileal resection)• Bacterial over growth • Decrease intestinal cells for absorption • Failure of synthesis of apoproteins

(abetalipoproteinemia)

Causes of abnormal lipids digestion

20

Errors of lipid digestion and absorption

1. Steatorhoea

stool fat > 5 gm per day

2. Chyluria (milky urine)

Abnormal connections between lymphatics and urinary system.

21

Fate of absorbed lipids

1. Storage

2. Energy production

3. Gluconeogenesis

4. Synthesis of

• Cellular structures

• Biological active compounds eg. Prostaglandins

22

Body lipids

Tissue lipidsAdipose tissue lipid

(depot fat)

WhiteUnder skin &breast Around vital organs

BrownMitochonderiaCytochromes

BVs

23

Fat Storage

• Mainly as triacylglycerols (triglycerides) in adipose cells

• Constitute 84% of stored energy

24

25

MITOCHONDRION

cell membrane

FA = fatty acidLPL = lipoprotein lipaseFABP = fatty acid binding protein

ACS

FABP

FABPFA

3

FABPacyl-CoA

4

CYTOPLASM

CAPILLARY

LPL

lipoproteins

2

FAFA

1

albuminFA FA

FA

From fat cell

carnitinetransporter

acyl-CoA

5

Overview of fatty acid degradation

ACS = acyl CoA synthetase

acetyl-CoA TCAcycle

-oxidation6

7

2626

I- Lipolysis

A- Definition:

-Lipolysis is the hydrolysis of triacylglycerols in adipose tissue into glycerol and fatty acids.

Triglycerides Glycerol + 3 free fatty acids

B- Steps:

- Lipolysis is carried out by a number of lipase enzymes, which are present in adipose tissue. These are:

1. Hormone sensitive triacylglycerol lipase.

2. Diacylglycerol lipase.

3. Monoacylglycerol lipase.

2727

Triacylglycerol

Hormone-sensitivetriacylglycerol lipase

diacylglycerol + free fatty acids

Diacylglycerol lipase

Glycerol +free fatty acids

Monoacylglycerollipase

monoacylglycerols + free fatty acids

28

Lipolysis products

Fatty acids Glycerol

29

Fate of fatty acids

OxidationIn tissues

Resterficationin adipose tissue

30

Fate of glycerol

Glucose by gluconeogenesis,

Pyruvate by glycolysis

Triacylglycerols by lipogenesis.

31

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

32

Note

• In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.

3333

Regulation of lipolysis

34

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.

35

Effect of hormones on lipolysis

• Lipolytic Hormones:

epinephrine

norepinephrine

adrenocorticotropic hormone (ACTH)

thyroid stimulating hormone (TSH)

Glucagon etc.

• Antilipolytic Hormones: insulin

36

Causes of excessive lipolysis:

• - In conditions where the need for energy is increased e.g.:

• 1- Starvation.

• 2- Diabetes mellitus.

• 3- Low carbohydrate diet.

37

Oxidation of fatty acids

• Beta oxidation (major catabolic pathway and never occurs in the brain)

• Alpha oxidation

• Omega oxidation

(Minor pathways and occurs in the brain)

38

Beta Oxidation

• Cleavage of fatty acids to acetate in tissues

• Occurs in the mitochondria of liver, kidney and heart

• Never occur in the brain•Fatty acid catabolism can be subdivided into 3 stages.

39

Stage 1 Activation of FAs

• Acyl-CoA Synthetase (Thiokinase), which locates in 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

40

Key points of FA activation

1. Irreversible

2. Consume 2 ~P

3. Site: cytosol

41

Stage 2Transport of acyl CoA into the

mitochondria ( rate-limiting step)

• Carrier: carnitine

42

• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

43

• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

2.Transport into Mitochondrial Matrix

Carnitine acylcarnitine transferase I

Carnitine acylcarnitine transferase II

44

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

45

Step 1. Dehydrogenate

H3C (CH2)n C C C SCoA

H

H

H

H O


H

H O

FADH2

FAD

Fatty acyl-CoA

acyl-CoA dehydrogenase

trans-¦¤2-enoyl-CoA

46

Step 2. Hydration


H

H O


H

O

H2O

OH

Trans-¦¤2-enoyl-CoA

H

H 3-L-Hydroxyacyl-CoA

enoyl-CoA Hydratase

47

Step 3. Dehydrogenate


H

OOH

H3C (CH2)n C CH2 C SCoA

OO

NADH + H+

NAD+

H

H 3-L-Hydroxyacyl-CoA

hydroxyacyl-CoAdehydrogenase

β -Ketoacyl-CoA

48

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

49

The β-oxidation pathway is cyclic

50

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

51

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.

52

-Oxidation of Myristic(C14) Acid

53

-Oxidation of Myristic (C14) Acid

7 Acetyl CoA

6 cycles

54

Cycles of -Oxidation

The length of a fatty acid• Determines the number of oxidations and the

total number of acetyl CoA groups

Carbons in Acetyl CoA -Oxidation CyclesFatty Acid (C/2) (C/2 –1)12 6 514 7 616 8 718 9 8

55

ATP for Myristic Acid C14

ATP production for Myristic(14 carbons):Activation of myristic acid -2 ATP

7 Acetyl CoA7 acetyl CoA x 12 ATP/acetyl CoA 84 ATP

6 Oxidation cycles 6 NADH x 3ATP/NADH 18 ATP6 FADH2 x 2ATP/FADH2 12 ATP

Total 102 ATP

56

Oxidation of Special Cases (monounsaturated fatty acids)

57

Odd Carbon Fatty Acids(13C)

CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA

5 Cycles

5 CH3COSCoA + CH3CH2COSCoA

Propionyl CoA

CO2H

COSCoA

H-C-CH3

CO2H

COSCoA

CH3-C-HHO2CCH 2CH2COSCoA

D-MethylmalonylCoA

L-MethylmalonylCoA

Succinyl CoA

TCA Cycle

Propionyl CoA CarboxylaseATP/CO2

EpimeraseMutase

Vit. B12

58

OHCH3 C

O

CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2

CoAC

O


CoAC

O

CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH CH2

OH

CoAC

O

CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH CH2

O

CH2CoAC

O

CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH

O

CoA

CoAC

O


NADH

FADH

2

2 ATP

59

SUMMARY OF ENERGY YIELD

PROCESSATP

USEDENERGY

YIELDATP EQUIVALENT

ACTIVATION2

OXIDATION FADH2 2 ATPs

OXIDATION NADH 3 ATPs

CITRIC ACID CYCLE

Acetyl CoA 12 ATPs

60

SUMMARY OF ENERGY YIELD Lauric acid (C12)

PROCESSATP

USEDENERGY YIELD

ATP EQUIVALENT

ACTIVATION2

OXIDATION 5 FADH2 10 ATPs

OXIDATION 5 NADH 15 ATPs

CITRIC ACID CYCLE

6 Acetyl CoA 72 ATPs

TOTAL 95 ATPs

61

PALMITIC ACID (16 C)

PROCESSATP

USEDENERGY YIELD

ATP EQUIVALENT

ACTIVATION2



CITRIC ACID CYCLE


TOTAL 129 ATPs

62

STEARIC ACID (18 C)

PROCESSATP

USEDENERGY YIELD

ATP EQUIVALENT

ACTIVATION2



CITRIC ACID CYCLE


TOTAL 146 ATPs

63

II- α-Oxidation:• This types of oxidation occurs in α position and

characterized by:1- It is mechanism mainly for branched chain fatty

acid, which is methylated at β position.2- It is specific for oxidation of phytanic acid.3- It is minor pathway for fatty acid oxidation.4- It occurs mainly in brain and nervous tissues.• In α-oxidation, there is one carbon atom removed

at a time from α position.• It dose not require CoASH and dose not generate

high energy phosphate.

64

R - CH2 - CH - CH2 - COOH R - CH2 - CH - CH - COOH

CH3

[O]

HydroxylaseCH3 OH

-hydroxyadd

R - CH2 - CH - C - COOH

CH3 O-keto acid

2H

Dehydrogenase

R - CH2 - CH - COOH

CH3

Lower chain F.A.

Oxidativedecarboxylation

CO2 [O]

Propionyl ~ CoA + Acyl ~ CoA -Oxidation-Oxidation

Refsum’s disease:1- This is inherited deficiency of enzymes responsible for α-oxidation of phytanic acid. This leads to accumulation of phytanic acid in serum and nervous tissue and produce nervous damage e.g. deafness and blindness.

65

ω-Oxidation

1. It is oxidation of terminal CH3 group of fatty acid.

2. It produces dicarboxylic fatty acids. By β-oxidation, they are converted to adipic acid (6 carbons) and suberic acid (8 carbons).

3. It is a minor pathway for fatty acid oxidation and used for oxidation of long chain fatty acids.

CH3 - CH2 CH2 -COOH

HOOC - CH2 CH2 -COOH

HOOC - (CH2)4 - COOHAdipicacidHOOC - (CH2)6 - COOHSubericacid

-Oxidation

Repeated -Oxidation(Aoetyl - CoA)

Dicarboxylicacid

66

67

Ketone Bodies

68

Formation and Utilization

• Ketone bodies are:

1. water-soluble fuels

2. Normally exported by the liver

3. overproduced during fasting or in untreated diabetes mellitus.

69

Types

1-

2-

3-

70

The formation of ketone bodies (Ketogenesis)

Location: hepatic mitochondria

Material: acetyl CoA

Rate-limiting enzyme: HMG-CoA synthase

71

72

Utilization of ketone bodies (ketolysis) Occurs at extrahepatic tissues

Succinyl-CoA transsulfurase

73

HSCoAATP

AMP PPi

Acetoacetate thiokinase

-

Occurs at extrahepatic tissues due toLack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver.

74

The significance of ketone bodies

• Ketone bodies are water soluble, they are convenient to transport in blood, and readily taken up by non-hepatic tissues

☻ In the early stages of fasting, the use of ketone bodies by heart, skeletal muscle conserves glucose for support of central nervous system.

☻With more prolonged starvation, brain can take up more ketone bodies to spare glucose consumption

• High concentration of ketone bodies can induce ketonemia and ketonuria, and even ketosis and acidosis

When carbohydrate catabolism is blocked by a disease of diabetes mellitus or defect of sugar source, the blood concentration of ketone bodies may increase,the patient may suffer from ketosis and acidosis

75

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

76

Ketosis consists of ketonemia, ketonuria and smell of acetone in breath

77

Causes for ketosis

• Severe diabetes mellitus

• Starvation

• Hyperemesis (vomiting) in early pregnancy

78

CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid

CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid

OH

Concentration of acetoacetic acid can result in metabolic acidosis affinity of Hb for O2 coma death

Metabolic Acidosis in Untreated Diabetes Mellitus

Lipogenesis

8080

A- Definition:

- Lipogenesis is the synthesis of triacylglycerol from fatty acids (acyl CoA) and glycerol (glycerol-3-phosphate).

B- Steps:

1- Activation of fatty acids into acyl CoA:

81

2- Synthesis of glycerol-3- phosphate:

82

3-Formation of TAG

8383

Regulation of lipogenesis

After meal, lipogenesis is stimulated:

- Insulin is secreted which stimulates glycolysis. Glycolysis supplies

dihydroxyacetone phosphate that converted into glycerol-3-phosphate

in adipose tissue, so lipogenesis is stimulated.

During fasting lipogenesis is inhibited:

- Anti-insulin hormones are secreted. These inhibit lipogenesis and

stimulate lipolysis

84

Fatty Acid Biosynthesis

85

1. Cytoplasmic or extramitochonderial (de novo)

synthesis

2. Microsomal pathway (aerobic elongation

pathway & ∆9 Unsaturation)

3. Mitochondrial (anaerobic elongation )

86

1. Palmitic Acid Synthesis

• Location: cytosol of liver,lactating mammary glands and adipose tissue. Precursor: acetyl CoA

• Other materials: ATP, NADPH, CO2

• Main product is palmitate (C16)• Problem:

» Most acetyl CoA produced in mitochondria» Acetyl CoA unable to traverse mitochondrial

membrane

87

Reactivity of acetyl Coenzyme A

NucleoNucleophilic acyl substitutionphilic acyl substitution

CHCH33CCSCoASCoA

OOHYHY••••

CHCH33CC

OO

YY •••• ++ HHSCoASCoA

Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent)

88

89

can react via enolcan react via enol

CHCH33CCSCoASCoA

OO

Acetyl coenzyme A reacts with biological electrophiles at its α carbon atom

CCSCoASCoA

OHOH

HH22CC

EE++

CHCH22CCSCoASCoA

OO

EE

Reactivity of acetyl Coenzyme A

90

Citrate Shuttle Or Citrate-pyruvate cycle

Citrate syntheaseATP-Citrate lyase

Malic enzyme

Glycolysis

+ CO2

Pyruvate carboxylase

91

The sources of NADPH are as follows:

1-Pentose phosphate pathway3- Cytoplasmic isocitrate dehydrogenase

3-Malic enzyme

92

Process of synthesis:

(1) Formation of Malonyl Coenzyme A (Carboxylation of Acetyl CoA)

(2) Repetitive steps catalyzed by fatty acid synthase

93

(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

94

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.

95

acetyl-CoA + HCO3 + H+

acetyl-CoA carboxylase (biotin)

malonyl-CoA

long chain acyl-CoA

ATP ADP + Pi

glucagon insulin

citrateisocitrate

96

• Regulation of Acetyl carboxylase– Global

（ + ） insulin（ - ） glucagon（ - ） epinephrine

– Local（ + ） Citrate（ - ） Palmitoyl–CoA（ - ） AMP

Regulation of Fatty Acid Synthesis

97

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

98

99

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)

100

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.

101

Fatty acid synthase complex

102

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

103

acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+

palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O

The overall reaction of synthesis:

104

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

105

Routes of synthesis of other fatty acids

106

2. Elongation of palmitate

Elongation beyond the 16-C length of the palmitate occurs in mitochondria and endoplasmic reticulum (ER).

107

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.

108

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

109

Desaturases introduce double bonds at specific positions in a fatty acid chain.

110

Orlistat: A Fatty Acid Synthase (FAS) Inhibitor

Anti-obesity (Inhibitspancreatic lipase in GIT)

Inhibits thioesterase domain of FAS

Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis

Metabolism of phospholipids

112

PhospholipidsPhospholipids• Structure

– Glycerol + 2 fatty acids + phosphate group

• Functions– Component of cell

membranes– Lipid transport as part of

lipoproteins• Food sources

– Egg yolks, liver, soybeans, peanuts

113

• Phospholipid refers to phosphorous-containing lipids.

Phospholipids

Glycerophospholipids

Sphingolipids

114

Phospholipids

Glycerol as alcoholSphingosine as

alcohol

SphingomyelineNon nitogenous base Nitrogenous base

Cephalin

Lecithin

Lipositol2nd messenger

Phosphatidic acid

Cardiolipin2phosphatidic acidLiked by glycerol

Phosphatidyl serine

Lysophospholipid

Plasmalogen

115

Classification and Structure of Glycerophospholipids

• Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base.

116

Phosphatidylcholine

fatty acids

nitrogenous base

glycerol

117

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

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In general, glycerophospholipids contain a saturated fatty acid at C-1 and an unsaturated fatty acid (usually arachidonic acid) at C-2.

119

Some common glycerophospholipid

120

Some common glycerophospholipid (continue)

121

Synthesis of Glycerophospholipid

Location:

All tissue of body, especially liver & kidney

Endoplasmic reticulum

Pathways:

1- CDP-diacylglycerol pathway

2- Diacylglycerol pathway

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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

123

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

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CDP-Diacylglycerol pathway

PhosphotidateCTP

PPi

CDP-diacylglycerol

CMP

CMP

CMP

Glycerol 3-phosphate

G

Phosphatidyl serinePhosphatidyl inositol

Phosphatidyl glycerol

Diphosphatidyl glycerol(cardiolipin)

SerineInositol

Dihydroxyacetonephosphate

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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

Snake venom

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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

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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

128

Metabolism of sphingolipids

• Palmitic acid + serine Called Sphingosine

• Sphingosine + Fatty acid Called ceramide

• Ceramide + Choline Called Sphingomylein

129

130

131

Respiratory Distress Syndrome

Most frequently seen in premature infants

Also called hyaline membrane disease

Failure to produce sufficient dipalmitoyl phosphatidylcholine,which normally is found in the extracellular fluid surroundingalveoli; decreases surface tension of fluid to prevent lung collapse

Treatment in infants born before 30 weeks includes

administration of artificial lung surfactant (e.g., Exosurf orPumactant)

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Glycolipids

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Ceramide Cerebroside

Sulphatides Gangliosides

Sulphate+ one or more of sialic acid (eg NANA or N acetyl galactos amine

+ galactose

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Synthesis of Gangliosides

CH3(CH2)12CH=CH-CH-CH-CH2OH

CH3(CH2)nCONH

OH

Ceramide

CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar

CH3(CH2)nCONH

OH

Cerebroside

Ganglioside

trans

transGlucose orgalactose

Ceramide - Sugar - Sugar - GalNAc - Gal

NANNAN = N-acetylneuraminateGalNAc = N-acetylgalactose

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Lipid Storage Diseases(Gangliosidoses)

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Tay-Sachs Disease

Ceramide - O - Glucose - Galactose - N-Acetylgalactose

Hexoseaminidase Acatalyzes cleavage of this glycoside linkage

GM2 (a ganglioside):

Autosomal recessive disorder characterized by deficiencyof hexoseaminidase A; accumulation of gangliosides in brainMost prevalent in Jews from Eastern EuropeFor further information see: http://www.marchofdimes.com/professionals/681_1227.asp

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Other Gangliosidoses

Gaucher’s disease:

Fabry’s disease:

Nieman-Pick disease:

Ceramide - O - Glucose

Ceramide - O - Glucose - O - Galactose - O - Galactose

Ceramide - Phosphate - Choline

-glucosidase

-galactosidase

sphingomyelinase

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• Eicosanoid horomones are synthesized from arachadonic acid (20:4)– Prostaglandins

• 20-carbon fatty acid containing 5-carbon ring

• Prostacyclins

• Thromboxanes

– Leukotrienes• contain three conjugated double bonds

Eicosanoid Hormones

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Eicosanoid Hormones

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Cholesterol MetabolismCholesterol Metabolism

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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.

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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

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Cholesterol ester

OCR

O

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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

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Acetyl-CoA is the direct and the only carbon source.

146HMG CoA reductase is the rate-limiting enzyme

Acetoacetyl-CoA

Acetyl-CoAHMG-CoA

147The total process of cholesterol de novo synthesis

148

Regulation of cholesterol synthesis

MVAHMG CoA reductase

cholesterol

bile acid

fasting Glucagon

after meal insulin thyroxine

HMG CoA

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Transformation and excretion of cholesterol

Steroidhormones

Bile acids

Cholesterol

Vitamin D

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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.

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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.

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Classification of bile acids

Classification Free bile

acidsConjugated bile acids

Primary bile acids

Cholic acidGlycocholic

acidTaurocholic 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

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(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

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HO

OH

H

COOH

HO H

COOH

deoxycholic acid lithocholic acid

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(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.

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(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.

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2. Conversion of cholesterol into steroid hormones

• Tissues: adrenal cortex, gonads

• Steroid hormones: cortisol (glucocorti-coid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol

158Steroids derived from cholesterol

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3. Conversion into 7-dehydrocholesterol

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Esterification of cholesterol

• in cells

HO OCR

O

cholesterol cholesteryl ester

acyl CoA cholesterol

acyl transferase(ACAT)

acyl CoASHCoA

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in plasma

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Plasma Lipoproteins

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Plasma lipids

1. Cholesterol 140-220 mg/dl (70% CE

and 30% free cholesterol)

2. Phospholipids 150-200 mg/dl

3. Triacylglycerol 50-155 mg/dl

4. FFA 6-16 mg/dl

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Structure

165

Types and Separation

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Classification of plasma lipoproteins

1. electrophoresis method:

- Lipoprotein fast

pre -Lipoprotein

-Lipoprotein

CM (chylomicron) slow

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2. Ultra centrifugation method：

high density lipoprotein (HDL) high

low density lipoprotein ( LDL)

very low density lipoprotein ( VLDL)

CM (chylomicron ) low

168

Composition

169electron microscope

170

－＋

Origin CM

LDL VLDL HDL

Pre-

CM

Separation of plasma lipoproteins by electrophoresis on agarose gel

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§ 5.3 Structure

172

§ 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

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§ 5.5 Apolipoproteins

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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.

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Functions• 1- Lipids are water insoluble compounds. Thus they cannot

be transported in plasma

• 2- Lipids are conjugated to proteins to form lipoproteins which are water soluble and can be transported in plasma.

• 3- These proteins are synthesized by the liver and called: apolipoproteins. They are 5 classes: A, B, C, D and E.

• 4- Failure of liver to synthesize apolipoproteins leads to accumulation of fat in liver and this condition called: fatty liver.

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1. CM

• Chylomicrons are formed in the intestinal mucosal cells and secreted into the lacteals of lymphatic system.

177

Cholesterol phospholipids

Triacylglycerols andcholesteryl esters

Apolipoproteins structure of CM

178

Metabolism of Chylomicrons

179

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

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2. VLDL

• Very low density lipoproteins (VLDL) are synthesized in the liver and produce a turbidity in plasma.

181

Metabolism of LDL and VLDL

182

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

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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.

184

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.

185

186

Internalization Lysosomal hydrolysisLDL binding

LDL receptors

Cholesterolester

protein

LDL

Cholesterol

Cholesteryloleate

Amino acids

187

Michael Brown and Joseph Goldstein were awarded Nobel prize in 1985 for their work on LDL receptors.

188

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.

189

4. HDL

• LDL variety is called “ bad cholesterol” whereas HDL is known as “ good cholesterol” .

190

VLDL LDL

HDL

Cholesterol

HeartLiver

“BAD”

Deposit

Excretion

“Good”

Forward and reverse cholesterol transport

191

Reverse cholesterol transport

• Cholesterol from tissues reach liver, and is later excreted. This is called reverse cholesterol transport by HDL.

192

Metabolism of HDL

193

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CETP

• Cholesterol ester transfer protein (CETP) transfer cholesterol ester in HDL to VLDL and LDL.

195

Summary of HDL

• Formation site: liver and intestine

• Function: transport cholesterol from peripheral tissues to liver

196

summary of lipoprotein metabolism

197

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↑

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Role of Ox LDL in plaque formation and atherosclerosis

199

200

2- Secondary hyperlipoproteinemia:These abnormalities are associated with other diseases as:a) Diabetes mellitus. b)Hypothyroidism.c) Nephrotic syndrome.d) Obesity.e) Obstructive jaundice.

B- Hypolipoproteinemia:1) Abetalipoproteinemia:- Characterized by absence of LDL (β-lipoprotein). It is

associated with low concentrations of chylomicrons and VLDL.

2) Tangier disease:a- Due to deficiency of LCAT enzyme.b- Characterized by low concentration of HDL with

accumulation of cholesterol in tissues.

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FATTY LIVER

I. Definition:-This is an accumulation of abnormal amount of fat in the liver for a long time with subsequent compression of liver cells.

II- Causes:

A- Over mobilization of fat from extrahepatic tissue to the liver.

B- During high carbohydrate diet.

C- Under mobilization of fat from the liver to the plasma.

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A. Causes of over mobilization of fat from extrahepatic tissue to the liver:

1- During high fat diet.

2- Due to excessive lipolysis as in carbohydrate low diet, starvation and diabetes mellitus.

B. High carbohydrate diet:

- On high carbohydrate diet, liver is first saturated with glycogen, then any further amount of carbohydrate will be converted to triacylglycerols (lipogenesis).

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C. Causes of under mobilization of fat from liver to the plasma:

- This is due deficiency any factor essential for plasma lipoproteins formation.

These factors are:1- Decreased synthesis of apoprotein (lipoprotein).2- Failure in formation of phospholipids.3- Failure in conjugation of apoprotein with triacylglycerols

or phospholipids.4- Failure in secretion of lipoprotein from liver to plasma.5- Liver poisons: As carbon tetrachloride, chloroform, lead

and arsenic. They cause fatty liver either by:a- Inhibition of formation of apoprotein.b- Inhibition of conjugation of apoprotein with lipids.c- Inhibition of secretion of lipoprotein.6- Alcoholism: Ethanol stimulates lipogenesis, inhibiting fatty

acid oxidation.

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Lipid Metabolism.ppt

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