Lipid Metabolism 3yj57
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الحرية ال تمنحها الحرية نبت ينمو
هيئات البر الخيرية بدماء حرة وزكية
فهيا معا نعلم العالم اسمى معانى الحرية قيمة كل امرئ ٍ ما يحسن ،والعاطل صفر ،والفاشل ممقوت ،والمخفق رخيص .
ر ِّكز اهتمامك على عمل واحد ،وانغمس فيه واحترق به وأعشقه لتكن مبدعا. ال تضق ذرعا بالمحن فإنها تصقل الرجال ،وتقدح العقل ،وتشعل الهمم.
االقسام الرئيسية للكيمياء الحيوية فى القرأن الكريم -1سكريات او كربوهيدرات ك آل َي ًة لِّ َق ْو ٍم َيعْ ِقلُو َن ِيل َواألَعْ َنا ِ ومِن َث َم َرا ِ ون ِم ْن ُه َس َكرً ا َو ِر ْز ًقا َح َس ًنا إِنَّ فِي َذلِ َ ب َت َّتخ ُِذ َ ت ال َّنخ ِ النحل -سورة - 16آية 67
-2اللحوم او البروتينات ِين َّللا َعلَى َما َه َدا ُك ْم َو َب ِّ ِ ِر ْالمُحْ سِ ن َ َّللا لُحُو ُم َها َوال ِد َماؤُ َها َولَكِن َي َنال ُ ُه ال َّت ْق َوى مِن ُك ْم َك َذلِ َ ك َس َّخ َر َها لَ ُك ْم لِ ُت َك ِّبرُوا َّ َ لَن َي َنا َل َّ َ الحج -سورة - 22آية 37
-3الدهون ون َو ُّدوا لَ ْو ُت ْدهِنُ َفي ُْد ِه ُن َ
القلم -سورة - 68آية 9
ون •أ َف ِب َه َذا ْال َحدِي ِ ث أَن ُتم م ُّْد ِه ُن َ
الواقعة -سورة - 56آية 81
ُ ور َس ْي َنا َء َتنب ُ ِين ُت ِبال ُّدهْ ِن َوصِ ب ٍْغ لِّ ْْل ِكل َ • َو َ ِ َج َر ًة َت ْخ ُر ُج مِن ط ِ
المؤمنون -سورة - 23آية 20
2
Lipid Metabolism By Dr. Gamil Abdalla
3
Course outlines 1. 2. 3. 4. 5. 6. 7.
Lipid digestion and absorption and their errors Fate of absorbed lipids Lipolysis and Lipogenesis Fatty acid oxidation and synthesis Ketogenesis and ketolysis Cholesterol and Lipiprotein metabolis Fatty liver 4
5
• Lipid family – Triglycerides (fats & oils) – Phospholipids – Sterols (cholesterol) – cholesterol esters are digested by esterase to fatty acids and cholesterol which absorbed as such
6
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
7
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
8
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
9
Bile • Produced in liver, stored in gallbladder • Alkaline solution composed of: – Bile salts – Cholesterol – Lecithin – Bilirubin
• Responsible for fat emulsification 10
Mixed micelle formed by bile salts, triacylglycerols and pancreatic lipase. 11
Digestion of TG • Bile salts emulsify lipids • Pancreatic lipase acts on triglycerides – Triglycerides fatty acids
2 monoglyceride + 2
• Pancreatic colipase – Activated by trypsin – Interacts with triglyceride and pancreatic lipase • Improves activity of pancreatic lipase 12
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)
13
Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli
Bile Salts
Dietary Fat (large TG droplet)
Lipase
2-Monoglyceride + 2 FFA
Lipid emulsion
14
Emulsification • Produces small lipid spheres – Greater surface area
• Lipases attack TG at 1 and 3 positions G Fatty Acid1 l y c e Fatty Acid2 r o l Fatty Acid3 Triglyceride
Lipase 2 H20
G l y c Fatty Acid2 e r o l 2-Monoglyceride
+
Fatty Acid1 Fatty Acid3
15
2 Free Fatty Acids
1
3
2
4
16
Digestion of phospholipids PLA 1
PLA 2
PLc
PLD
17
LipidAbsorption Absorption Lipid Intestinal Wall
Liver
Lumin
Glycerol
Glycerol
Short chain FA
Short chain FA
Portal circulation
Bile salts
Long chain FA Chylomicrones Lacteal
Systimic Circulation
Protein
Cholesterol Phospholipids
Micelles
Thoracic Duct
Triacylglycerols
Monoacylglycerol
Bile salts + Monoacylglycerol + Long chain FA + Cholesterol + Phospholipids
18
Causes of abnormal lipids digestion • •
• • • •
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) 19
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.
20
Fate of absorbed lipids 1. 2. 3. 4. • •
Storage Energy production Gluconeogenesis Synthesis of Cellular structures Biological active compounds eg. Prostaglandins 21
Body lipids
Tissue lipids
Adipose tissue lipid (depot fat)
White Under skin &breast Around vital organs
Brown Mitochonderia Cytochromes BVs
22
Fat Storage • Mainly as triacylglycerols (triglycerides) in adipose cells • Constitute 84% of stored energy
23
24
CAPILLARY lipoproteins
MITOCHONDRION
FABP FA
LPL
FA FA albumin FA 1
3
FA
TCA cycle 7 -oxidation 6 acyl-CoA
acetyl-CoA
2
FA FABP
4 acyl-CoA FABP
CYTOPLASM
A C S 5
carnitine transporter
From fat cell cell membrane
FA = fatty acid LPL = lipoprotein lipase FABP = fatty acid binding protein ACS = acyl CoA synthetase
Overview of fatty acid degradation 25
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. 26 26
Triacylglycerol
Hormone-sensitive triacylglycerol lipase
diacylglycerol + free fatty acids Diacylglycerol lipase
Glycerol + free fatty acids
Monoacylglycerol lipase
monoacylglycerols + free fatty acids
27 27
Lipolysis products
Fatty acids
Glycerol 28
Fate of fatty acids
Oxidation In tissues
Resterfication in adipose tissue 29
Fate of glycerol
Glucose by gluconeogenesis,
Pyruvate by glycolysis
Triacylglycerols by lipogenesis.
30
glycerol metabolism Place: liver, kidney, intestine g ADP CH2OH CH2OH ATP 3-phlycerol deh osph yd r o HO C H a HO C H g en t e glycerol as e CH2O P kinase CH2OH NAD+ CH2OH Glycerol L-Glycerol 3-phosphate O C NADH+H+ Glycolysis
CHO H C OH
Glyconeogenesis
CH2O P D-Glyceraldehyde 3-phosphate
CH2O P Dihydroxyacetone triose phosphate phosphate isomerase
31
Note • In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.
32
Regulation of lipolysis
33 33
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.
34
Effect of hormones on lipolysis • Lipolytic Hormones:
epinephrine norepinephrine adrenocorticotropic hormone (ACTH) thyroid stimulating hormone (TSH) Glucagon etc.
• Antilipolytic Hormones: insulin 35
Causes of excessive lipolysis: • - In conditions where the need for energy is increased e.g.: • 1- Starvation. • 2- Diabetes mellitus. • 3- Low carbohydrate diet.
36
Oxidation of fatty acids • Beta oxidation (major catabolic pathway and never occurs in the brain)
• Alpha oxidation (Minor pathways and occurs in the brain)
• Omega oxidation
37
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.
38
Stage 1 Activation of FAs • Acyl-CoA Synthetase (Thiokinase), which locates in the cytoplasm, catalyzes the activation of long chain fatty acids.
O R C
+ HSCoA O
Fatty acid
AMP + PPi O Mg2+ R C acyl-CoA S CoA synthetase acyl-CoA
ATP
39
Key points of FA activation 1. Irreversible 2. Consume 2 ~P 3. Site: cytosol
40
Stage 2 Transport of acyl CoA into the mitochondria ( rate-limiting step) • Carrier: carnitine
41
• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix
42
2.Transport into Mitochondrial Matrix • Carnitine carries long-chain activated fatty acids into the mitochondrial matrix
Carnitine acylcarnitine transferase I
Carnitine acylcarnitine transferase II
43
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 44
Step 1. Dehydrogenate
H3C
H
H
O
C
C
C
H FAD
H
(CH2)n
SCoA Fatty acyl-CoA
acyl-CoA dehydrogenase FADH2
H3C
(CH2)n
C H
H
O
C
C
SCoA
trans-¦¤2-enoyl-CoA 45
Step 2. Hydration H3C
(CH2)n
C
H
O
C
C
Trans-¦¤2-enoyl-CoA
H H2O
H3C
(CH2)n
SCoA
enoyl-CoA Hydratase
OH H
O
C
C
C
H
H
3-L-Hydroxyacyl-CoA
SCoA
46
Step 3. Dehydrogenate
H3 C
OH H
O
C
C
C
H NAD+
H
3-L-Hydroxyacyl-CoA
(CH2)n
NADH + H+
hydroxyacyl-CoA dehydrogenase
O H3 C
(CH2)n
C
SCoA
O CH2
C
SCoA
β-Ketoacyl-CoA 47
Step 4. Thiolytic cleavage O H 3C
(CH2)n
C
O CH2
C
SCoA
β-Ketoacyl-CoA HSCoA
β-Ketothiolase
O H3 C
(CH2)n
C
O SCoA + CH3
Fatty acyl-CoA (2C shorter)
C
SCoA
Acetyl-CoA 48
The β-oxidation pathway is cyclic
49
Summary one cycle of the β-oxidation:
fatty acyl-CoA + FAD + NAD+ + HS-CoA →fatty acyl-CoA (2 C less) + FADH2 +
NADH + H+ + acetyl-CoA
50
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. 51
-Oxidation of Myristic(C14) Acid
52
-Oxidation of Myristic (C14) Acid
6 cycles
7 Acetyl CoA
53
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 Cycles Fatty Acid (C/2) (C/2 –1) 12 6 5 14 7 6 16 8 7 18 9 8 54
ATP for Myristic Acid C14 ATP production for Myristic(14 carbons): Activation of myristic acid 7 Acetyl CoA 7 acetyl CoA x 12 ATP/acetyl CoA 6 Oxidation cycles 6 NADH x 3ATP/NADH 6 FADH2 x 2ATP/FADH2 Total
-2 ATP 84 ATP 18 ATP 12 ATP 102 ATP 55
Oxidation of Special Cases (monounsaturated fatty acids)
56
Odd Carbon Fatty Acids(13C) CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA
TCA Cycle
CO2H Mutase
CH3-C-H
HO 2CCH2CH2COSCoA
Succinyl CoA
Epimerase
Vit. B12
COSCoA L-Methylmalonyl CoA
Propionyl CoA Carboxylase ATP/CO2
CO2 H H-C-CH3 COSCoA
D-Methylmalonyl CoA
57
O CH3 CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 2 ATP
C
OH
O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
CoA
C
FADH2
O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
OH CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH
O CH2
O
NADH
CoA
C
CoA
C O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH CH2
CoA
C
O
O CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH
CoA
CH2
C
CoA 58
SUMMARY OF ENERGY YIELD ENERGY YIELD
ATP EQUIVALENT
OXIDATION
FADH2
2 ATPs
OXIDATION
NADH
3 ATPs
CITRIC ACID CYCLE
Acetyl CoA
12 ATPs
PROCESS
ACTIVATION
ATP USED
2
59
SUMMARY OF ENERGY YIELD Lauric acid (C12) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
5 FADH2
10 ATPs
OXIDATION
5 NADH
15 ATPs
CITRIC ACID CYCLE
6 Acetyl CoA
72 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
95 ATPs
60
PALMITIC ACID (16 C) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
7 FADH2
14 ATPs
OXIDATION
7 NADH
21 ATPs
CITRIC ACID CYCLE
8 Acetyl CoA
96 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
129 ATPs 61
STEARIC ACID (18 C) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
8 FADH2
16 ATPs
OXIDATION
8 NADH
24 ATPs
CITRIC ACID CYCLE
9 Acetyl CoA
108 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
146 ATPs 62
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.
63
R - CH 2 - CH - CH2 - COOH
[O] Hydroxylase
CH 3
R - CH2 - CH - CH - COOH CH 3 OH -hydroxyadd Dehydrogenase
R - CH 2 - CH - COOH
CO2
CH3 Lower chain F.A. -Oxidation
[O]
2H
R - CH2 - CH - C - COOH Oxidative CH 3 O decarboxylation -keto acid
Propionyl ~ CoA + Acyl ~ CoA
-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. 64
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
HOOC - CH2
CH2 COOH -Oxidation CH2 Dicarboxylicacid COOH Repeated -Oxidation (Aoetyl- CoA)
HOOC - (CH2)4 - COOH Adipicacid HOOC - (CH2)6 - COOH Subericacid
65
66
Ketone Bodies
67
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.
68
Types
123-
69
The formation of ketone bodies (Ketogenesis) Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase
70
71
Utilization of ketone bodies (ketolysis) Occurs at extrahepatic tissues Succinyl-CoA transsulfurase
72
HSCoA ATP -
AMP PPi
Acetoacetate thiokinase
Occurs at extrahepatic tissues due to Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver. 73
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 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 74
Hepatocyte
Acetoacetate, β-hydroxybutyrate, acetone Ketone body formation Fatty Acetyl-CoA acids β-oxidation CoA
Citric Acid cycle
Ketone bodies exported as energy source for heart, skeletal muscle, kidney, and brain
oxaloacetate gluconeogenesis Glucose
Glucose exported as fuel for tissues such as brain 75
Ketosis consists of ketonemia, ketonuria and smell of acetone in breath 76
Causes for ketosis • Severe diabetes mellitus
• Starvation • Hyperemesis (vomiting) in early pregnancy
77
Metabolic Acidosis in Untreated Diabetes Mellitus CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid
OH CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid
Concentration of acetoacetic acid can result in metabolic acidosis affinity of Hb for O2 coma death 78
Lipogenesis
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:
80 80
2- Synthesis of glycerol-3- phosphate:
81
3-Formation of TAG
82
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
83 83
Fatty Acid Biosynthesis
84
1. Cytoplasmic or extramitochonderial (de novo)
synthesis 2. Microsomal pathway (aerobic elongation pathway & ∆9 Unsaturation)
3. Mitochondrial (anaerobic elongation ) 85
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
86
Reactivity of acetyl Coenzyme A Nucleophilic acyl substitution O
CH3CSCoA
HY ••
O
CH3C
Y •• + HSCoA
Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent) 87
88
Reactivity of acetyl Coenzyme A can react via enol O
OH H2C
CH3CSCoA
CSCoA E+
Acetyl coenzyme A reacts with biological electrophiles at its α carbon atom E
O CH2CSCoA
89
Citrate Shuttle Or Citrate-pyruvate cycle
Glycolysis
Citrate synthease
ATP-Citrate lyase
Pyruvate carboxylase Malic enzyme
+ CO2 90
The sources of NADPH are as follows: 1-Pentose phosphate pathway 3- Cytoplasmic isocitrate dehydrogenase 3-Malic enzyme
91
Process of synthesis: (1) Formation of Malonyl Coenzyme A (Carboxylation of Acetyl CoA) (2) Repetitive steps catalyzed by fatty acid synthase
92
(1) Carboxylation of Acetyl CoA O CH3 C SCoA + HCO3 acetyl-CoA
ATP
ADP + Pi biotin
acetyl-CoA carboxylase
O OOC CH2 C SCoA malonyl-CoA
Malonyl-CoA serves as the donor of twocarbon unit. 93
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.
94
glucagon ATP
insulin ADP + Pi
acetyl-CoA + HCO3 + H+ malonyl-CoA acetyl-CoA carboxylase (biotin) long chain acyl-CoA citrate isocitrate
95
Regulation of Fatty Acid Synthesis • Regulation of Acetyl carboxylase – Global （+） insulin （-） glucagon （-） epinephrine
– Local （+）Citrate （-） Palmitoyl–CoA （-） AMP 96
(2) Repetitive steps catalyzed by fatty acid synthase Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are: in bacteria catalyzed by seven separate enzymes. in mammals catalyzed by individual domains of a single large polypeptide. 97
98
Fatty acid synthase complex (multifunctional enzyme) • • • • • • • •
Acyl carrier protein (A) Acetyl-CoA-A transacetylase (AT) β-Ketoacyl-A synthase (KS) Malonyl-CoA-A transferase (MT) β-Ketoacyl-A reductase (KR) β-Hydroacyl-A dehydratase (HD) Enoyl-A reductase (ER) Thioesterase (TE)
99
AT
MT HD
Cys Subunit division
HS HS
KR A
Functional division
KS
ER
TE PhP HS HS
PhP
Cys
TE KS
A KR
ER
HD
MT
AT
A contains 4’-phosphopantotheine. 100
Fatty acid synthase complex
101
O
HS CH3 C S
CH 3 C S CoA O HS HS
A-HS KS-HS
OOC CH 2 C S CoA
O
HS CoA O
MT AT
HS CoA
OOC CH2 C S CH3 C S O
O CH3 (CH2)14 C O O
(After 7 rounds)
HS CH3 CH2 CH2 C S
TE
H2O
①
condensation KS CO 2
O O
CH3 C CH2 C S HS O
AT
CH3 CH2 CH2 C S HS
② ④
O
reduction NADP+
CH3 CH CH2 C S HS OH
ER
O NADPH + H+
CH3 CH CH C S HS
reduction
③
KR
NADPH + H+ NADP+
dehydration HD
102 H2O
The overall reaction of synthesis:
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+
palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O
103
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 A
Enzymes
Present as independent proteins
Multi-enzyme complex
Sequential units
2 carbon units split off 2 carbon units added, as 3 as acetyl CoA carbon malonyl CoA
Co-enzymes
NAD+ and FAD are reduced
NADPH used as reducing power 104
Routes of synthesis of other fatty acids
105
2. Elongation of palmitate Elongation beyond the 16-C length of the palmitate occurs in mitochondria and endoplasmic reticulum (ER).
106
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. 107
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
108
O 10 9
oleate 18:1 cis 9
C
OH
Desaturases introduce double bonds at specific positions in a fatty acid chain.
109
Orlistat: A Fatty Acid Synthase (FAS) Inhibitor Anti-obesity (Inhibits pancreatic lipase in GIT) Inhibits thioesterase domain of FAS Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis
110
Metabolism of phospholipids
Phospholipids • 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
112
• Phospholipid refers to phosphorouscontaining lipids. Glycerophospholipids Phospholipids Sphingolipids
113
Phospholipids
Sphingosine as alcohol
Glycerol as alcohol
Non nitogenous base
Nitrogenous base
Sphingomyeline
Phosphatidic acid
Cephalin
Cardiolipin 2phosphatidic acid Liked by glycerol
Lecithin
2nd
Lipositol messenger
Phosphatidyl serine
Lysophospholipid
Plasmalogen
114
Classification and Structure of Glycerophospholipids
• Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base.
115
glycerol
fatty acids
nitrogenous base
Phosphatidylcholine 116
甘油 glycerol 脂酰基
CH2 O
O R2
C
O
O
fatty acyl group
C CH2
H
C
R1
fatty acyl group 脂酰基
O O
P
Nitrogenous O X 含氮化合物 base
OH
The basic structure of glycerophospholipid 117
In general, glycerophospholipids contain a saturated fatty acid at C-1 and an unsaturated fatty acid (usually arachidonic acid) at C-2. 118
Some common glycerophospholipid
119
Some common glycerophospholipid (continue)
120
Synthesis of Glycerophospholipid Location: All tissue of body, especially liver & kidney Endoplasmic reticulum Pathways: 1- CDP-diacylglycerol pathway 2- Diacylglycerol pathway 121
The system of synthesis a. FA Glycerol
from carbohydrate
b. poly unsaturated fatty acid from plant oil c. choline ethanolamine serine inositol
from food or synthesis in body
d. ATP, CTP
e. Enzymes and cofactors 122
Diacylglycerol pathway CO2 HO CH2 CH COOH
HO CH2 CH2 NH2
3 SAM
HO CH2 CH2 N(CH3)3
Choline
Ethanolamine
NH2
Serine
ATP
ATP
ADP
ADP
P O CH2 CH2 N(CH3)3
P O CH2 CH2 NH2
Phosphocholine
Phosphoethanolamine CTP
CTP
PPi
PPi
CDP O CH2 CH2 NH2
CDP O CH2 CH2 N(CH3)3
CDP-choline
CDP-ethanolamine CO2
Phosphatidyl serine
DG
DG
CMP
CMP
Phosphatidyl ethanolamine
3 SAM
Phosphatidyl choline 123
CDP-Diacylglycerol pathway Dihydroxyacetone phosphate
Glycerol 3-phosphate
Phosphotidate CTP
G
PPi CDP-diacylglycerol Inositol CMP
Serine
Phosphatidyl glycerol CMP
CMP Phosphatidyl inositol
Diphosphatidyl glycerol (cardiolipin) Phosphatidyl serine 124
Degradation of glycerophospholipids by phospholipase Snake venom
A1 O A2 O R2
C
O
O
CH2 C CH2
C
R1 D
H
O O
P
O
X
OH C
125
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 126
Lysophospholipids, the products of Phospholipase A hydrolysis, are powerful detergents. O
O O R2
C
CH2 O
C
H
O C
R1 H2O
R2
P O
phospholipid
O
CH2
HO
O PLA2
CH2O
C
O
O X
C
O H
O
CH2O
P
C
R1
O X
O Lysophospholipid 127
Metabolism of sphingolipids • Palmitic acid + serine Called Sphingosine • Sphingosine + Fatty acid Called ceramide • Ceramide + Choline Called Sphingomylein
128
129
130
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 surrounding alveoli; decreases surface tension of fluid to prevent lung collapse Treatment in infants born before 30 weeks includes istration of artificial lung surfactant (e.g., Exosurf or
Pumactant)
131
Glycolipids
132
Ceramide + galactose Cerebroside Sulphate
Sulphatides
+ one or more of sialic acid (eg NANA or N acetyl galactos amine
Gangliosides
133
Synthesis of Gangliosides OH trans
CH3(CH2)12CH=CH-CH-CH-CH2OH CH3(CH2)nCONH
Ceramide
OH trans
CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar CH3(CH2)nCONH
Glucose or galactose
Cerebroside
Ceramide - Sugar - Sugar - GalNAc - Gal NAN = N-acetylneuraminate GalNAc = N-acetylgalactose
NAN
Ganglioside
134
Lipid Storage Diseases (Gangliosidoses)
135
Tay-Sachs Disease GM2 (a ganglioside): Ceramide - O - Glucose - Galactose - N-Acetylgalactose Hexoseaminidase A catalyzes cleavage of this glycoside linkage Autosomal recessive disorder characterized by deficiency of hexoseaminidase A; accumulation of gangliosides in brain Most prevalent in Jews from Eastern Europe For further information see: http://www.marchofdimes.com/professionals/681_1227.asp
136
Other Gangliosidoses Gaucher’s disease: Ceramide - O - Glucose -glucosidase Fabry’s disease: Ceramide - O - Glucose - O - Galactose - O - Galactose -galactosidase Nieman-Pick disease: Ceramide - Phosphate - Choline sphingomyelinase
137
Eicosanoid Hormones • 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
138
Eicosanoid Hormones
139
Cholesterol Metabolism
140
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. 141
2. Structure of cholesterol All steroids have cyclopentano penhydro phenanthrene ring system. H3C 21
22
18 CH3 12 19 CH3 1 2
HO
4
C
24
25
CH3
20
26
27 CH3
17 13
D 16
14
15
9 10
A
3
11
23
5
B 8 6
7 142
Cholesterol ester
O C
O
R 143
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 144
Acetyl-CoA is the direct and the only carbon source. 145
Acetyl-CoA HMG-CoA
Acetoacetyl-CoA
HMG CoA reductase is the rate-limiting enzyme 146
The total process of cholesterol de novo synthesis 147
Regulation of cholesterol synthesis
fasting
HMG CoA
Glucagon
HMG CoA reductase
after meal
insulin
MVA
thyroxine
cholesterol
bile acid
148
Transformation and excretion of cholesterol
Bile acids
Steroid hormones
Vitamin D Cholesterol
149
1. Conversion of Cholesterol into bile acid (1) Classification of bile acids The primary bile acids are synthesized in the liver from cholesterol. The 7hydroxylase is rate-limiting enzyme in the pathway for synthesis of the bile acids. 150
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.
151
Classification of bile acids Classification
Free bile acids
Cholic acid
Glycocholic acid
Taurocholic acid
Chenodeoxycholic acid
Glycochenodeoxycholic acid
Taurochenodeoxycholic acid
Deoxycholic acid
Glycodeoxycholic acid
Taurodeoxycholic acid
Lithocholic acid
Glycolithocholic acid
Taurolitho-cholic acid
Primary bile acids
Secondary bile acids
Conjugated bile acids
152
(2) Strcture of bile acids OH
COOH
COOH
12
3
HO
7
H cholic acid
OH
OH
HO
H
OH
glycocholic acid
HO
OH H chenodeoxycholic acid
CONHCH2COOH
HO
OH
H
CONHCH2CH2SO3H
OH
taurocholic acid
153
OH
HO
H deoxycholic acid
COOH
COOH
HO
H lithocholic acid
154
(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. 155
(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.
156
2. Conversion of cholesterol into steroid hormones • Tissues: adrenal cortex, gonads
• Steroid hormones: cortisol (glucocorticoid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol
157
Steroids derived from cholesterol
158
3. Conversion into 7-dehydrocholesterol
159
Esterification of cholesterol • in cells SHCoA acyl CoA O
HO
cholesterol
acyl CoA cholesterol R C O acyl transferase cholesteryl ester (ACAT)
160
in plasma
161
Plasma Lipoproteins
162
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
163
Structure
164
Types and Separation
165
Classification of plasma lipoproteins 1. electrophoresis method: - Lipoprotein
fast
pre -Lipoprotein -Lipoprotein CM (chylomicron)
slow
166
2. Ultra centrifugation method： high density lipoprotein (HDL) high low density lipoprotein ( LDL) very low density lipoprotein ( VLDL) CM (chylomicron ) low
167
Composition
168
electron microscope
169
CM
LDL
VLDL
HDL
－
＋
Origin
CM
Pre-
Separation of plasma lipoproteins by electrophoresis on agarose gel 170
§ 5.3 Structure
171
§ 5.4 Composition of lipoprotein CM
VLDL
LDL
HDL
<1.006
0.951.006
1.0061.063
1.0631.210
Protein
2
10
23
55
Phospholipids
9
18
20
24
Cholesterol
1
7
8
2
Cholesteryl esters
3
12
37
15
TG
85
50
10
4
Density(g/ml)
172
§ 5.5 Apolipoproteins
173
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. 174
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. 175
1. CM • Chylomicrons are formed in the intestinal mucosal cells and secreted into the lacteals of lymphatic system.
176
structure of CM
Apolipoproteins
phospholipids
Cholesterol
Triacylglycerols and cholesteryl esters
177
Metabolism of Chylomicrons
178
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 179
2. VLDL • Very low density lipoproteins (VLDL) are synthesized in the liver and produce a turbidity in plasma.
180
Metabolism of LDL and VLDL
181
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 182
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.
183
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
185
LDL receptors Cholesterol ester
protein
Cholesterol
LDL
Cholesteryl oleate
Amino acids LDL binding
Internalization
Lysosomal hydrolysis 186
Michael Brown and Joseph Goldstein were awarded Nobel prize in 1985 for their work on LDL receptors.
187
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.
188
4. HDL • LDL variety is called “ bad cholesterol” whereas HDL is known as “ good cholesterol” .
189
Liver
Heart VLDL
“Good” Excretion
“BAD” LDL Cholesterol Deposit
HDL
Forward and reverse cholesterol transport 190
Reverse cholesterol transport • Cholesterol from tissues reach liver, and is later excreted. This is called reverse cholesterol transport by HDL.
191
Metabolism of HDL
192
193
CETP • Cholesterol ester transfer protein (CETP) transfer cholesterol ester in HDL to VLDL and LDL.
194
Summary of HDL • Formation site: liver and intestine • Function: transport cholesterol from peripheral tissues to liver
195
summary of lipoprotein metabolism
196
Hyperlipidemias classification
Lipoprotein
Blood lipids
Ⅰ
CM
TAG↑ ↑ ↑ CH↑
Ⅱa
LDL
CH↑ ↑
Ⅱb
LDL, VLDL
CH↑ ↑ TAG↑ ↑
Ⅲ
IDL
CH↑ ↑ TAG↑ ↑
Ⅳ
VLDL
Ⅴ
VLDL, CM
TAG↑ ↑ TAG↑ ↑ ↑ CH↑ 197
Role of Ox LDL in plaque formation and atherosclerosis
198
199
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. 200
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 the201 plasma.
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). 202
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. 203
204
205
هيئات البر الخيرية بدماء حرة وزكية
فهيا معا نعلم العالم اسمى معانى الحرية قيمة كل امرئ ٍ ما يحسن ،والعاطل صفر ،والفاشل ممقوت ،والمخفق رخيص .
ر ِّكز اهتمامك على عمل واحد ،وانغمس فيه واحترق به وأعشقه لتكن مبدعا. ال تضق ذرعا بالمحن فإنها تصقل الرجال ،وتقدح العقل ،وتشعل الهمم.
االقسام الرئيسية للكيمياء الحيوية فى القرأن الكريم -1سكريات او كربوهيدرات ك آل َي ًة لِّ َق ْو ٍم َيعْ ِقلُو َن ِيل َواألَعْ َنا ِ ومِن َث َم َرا ِ ون ِم ْن ُه َس َكرً ا َو ِر ْز ًقا َح َس ًنا إِنَّ فِي َذلِ َ ب َت َّتخ ُِذ َ ت ال َّنخ ِ النحل -سورة - 16آية 67
-2اللحوم او البروتينات ِين َّللا َعلَى َما َه َدا ُك ْم َو َب ِّ ِ ِر ْالمُحْ سِ ن َ َّللا لُحُو ُم َها َوال ِد َماؤُ َها َولَكِن َي َنال ُ ُه ال َّت ْق َوى مِن ُك ْم َك َذلِ َ ك َس َّخ َر َها لَ ُك ْم لِ ُت َك ِّبرُوا َّ َ لَن َي َنا َل َّ َ الحج -سورة - 22آية 37
-3الدهون ون َو ُّدوا لَ ْو ُت ْدهِنُ َفي ُْد ِه ُن َ
القلم -سورة - 68آية 9
ون •أ َف ِب َه َذا ْال َحدِي ِ ث أَن ُتم م ُّْد ِه ُن َ
الواقعة -سورة - 56آية 81
ُ ور َس ْي َنا َء َتنب ُ ِين ُت ِبال ُّدهْ ِن َوصِ ب ٍْغ لِّ ْْل ِكل َ • َو َ ِ َج َر ًة َت ْخ ُر ُج مِن ط ِ
المؤمنون -سورة - 23آية 20
2
Lipid Metabolism By Dr. Gamil Abdalla
3
Course outlines 1. 2. 3. 4. 5. 6. 7.
Lipid digestion and absorption and their errors Fate of absorbed lipids Lipolysis and Lipogenesis Fatty acid oxidation and synthesis Ketogenesis and ketolysis Cholesterol and Lipiprotein metabolis Fatty liver 4
5
• Lipid family – Triglycerides (fats & oils) – Phospholipids – Sterols (cholesterol) – cholesterol esters are digested by esterase to fatty acids and cholesterol which absorbed as such
6
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
7
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
8
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
9
Bile • Produced in liver, stored in gallbladder • Alkaline solution composed of: – Bile salts – Cholesterol – Lecithin – Bilirubin
• Responsible for fat emulsification 10
Mixed micelle formed by bile salts, triacylglycerols and pancreatic lipase. 11
Digestion of TG • Bile salts emulsify lipids • Pancreatic lipase acts on triglycerides – Triglycerides fatty acids
2 monoglyceride + 2
• Pancreatic colipase – Activated by trypsin – Interacts with triglyceride and pancreatic lipase • Improves activity of pancreatic lipase 12
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)
13
Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli
Bile Salts
Dietary Fat (large TG droplet)
Lipase
2-Monoglyceride + 2 FFA
Lipid emulsion
14
Emulsification • Produces small lipid spheres – Greater surface area
• Lipases attack TG at 1 and 3 positions G Fatty Acid1 l y c e Fatty Acid2 r o l Fatty Acid3 Triglyceride
Lipase 2 H20
G l y c Fatty Acid2 e r o l 2-Monoglyceride
+
Fatty Acid1 Fatty Acid3
15
2 Free Fatty Acids
1
3
2
4
16
Digestion of phospholipids PLA 1
PLA 2
PLc
PLD
17
LipidAbsorption Absorption Lipid Intestinal Wall
Liver
Lumin
Glycerol
Glycerol
Short chain FA
Short chain FA
Portal circulation
Bile salts
Long chain FA Chylomicrones Lacteal
Systimic Circulation
Protein
Cholesterol Phospholipids
Micelles
Thoracic Duct
Triacylglycerols
Monoacylglycerol
Bile salts + Monoacylglycerol + Long chain FA + Cholesterol + Phospholipids
18
Causes of abnormal lipids digestion • •
• • • •
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) 19
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.
20
Fate of absorbed lipids 1. 2. 3. 4. • •
Storage Energy production Gluconeogenesis Synthesis of Cellular structures Biological active compounds eg. Prostaglandins 21
Body lipids
Tissue lipids
Adipose tissue lipid (depot fat)
White Under skin &breast Around vital organs
Brown Mitochonderia Cytochromes BVs
22
Fat Storage • Mainly as triacylglycerols (triglycerides) in adipose cells • Constitute 84% of stored energy
23
24
CAPILLARY lipoproteins
MITOCHONDRION
FABP FA
LPL
FA FA albumin FA 1
3
FA
TCA cycle 7 -oxidation 6 acyl-CoA
acetyl-CoA
2
FA FABP
4 acyl-CoA FABP
CYTOPLASM
A C S 5
carnitine transporter
From fat cell cell membrane
FA = fatty acid LPL = lipoprotein lipase FABP = fatty acid binding protein ACS = acyl CoA synthetase
Overview of fatty acid degradation 25
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. 26 26
Triacylglycerol
Hormone-sensitive triacylglycerol lipase
diacylglycerol + free fatty acids Diacylglycerol lipase
Glycerol + free fatty acids
Monoacylglycerol lipase
monoacylglycerols + free fatty acids
27 27
Lipolysis products
Fatty acids
Glycerol 28
Fate of fatty acids
Oxidation In tissues
Resterfication in adipose tissue 29
Fate of glycerol
Glucose by gluconeogenesis,
Pyruvate by glycolysis
Triacylglycerols by lipogenesis.
30
glycerol metabolism Place: liver, kidney, intestine g ADP CH2OH CH2OH ATP 3-phlycerol deh osph yd r o HO C H a HO C H g en t e glycerol as e CH2O P kinase CH2OH NAD+ CH2OH Glycerol L-Glycerol 3-phosphate O C NADH+H+ Glycolysis
CHO H C OH
Glyconeogenesis
CH2O P D-Glyceraldehyde 3-phosphate
CH2O P Dihydroxyacetone triose phosphate phosphate isomerase
31
Note • In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.
32
Regulation of lipolysis
33 33
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.
34
Effect of hormones on lipolysis • Lipolytic Hormones:
epinephrine norepinephrine adrenocorticotropic hormone (ACTH) thyroid stimulating hormone (TSH) Glucagon etc.
• Antilipolytic Hormones: insulin 35
Causes of excessive lipolysis: • - In conditions where the need for energy is increased e.g.: • 1- Starvation. • 2- Diabetes mellitus. • 3- Low carbohydrate diet.
36
Oxidation of fatty acids • Beta oxidation (major catabolic pathway and never occurs in the brain)
• Alpha oxidation (Minor pathways and occurs in the brain)
• Omega oxidation
37
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.
38
Stage 1 Activation of FAs • Acyl-CoA Synthetase (Thiokinase), which locates in the cytoplasm, catalyzes the activation of long chain fatty acids.
O R C
+ HSCoA O
Fatty acid
AMP + PPi O Mg2+ R C acyl-CoA S CoA synthetase acyl-CoA
ATP
39
Key points of FA activation 1. Irreversible 2. Consume 2 ~P 3. Site: cytosol
40
Stage 2 Transport of acyl CoA into the mitochondria ( rate-limiting step) • Carrier: carnitine
41
• Carnitine carries long-chain activated fatty acids into the mitochondrial matrix
42
2.Transport into Mitochondrial Matrix • Carnitine carries long-chain activated fatty acids into the mitochondrial matrix
Carnitine acylcarnitine transferase I
Carnitine acylcarnitine transferase II
43
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 44
Step 1. Dehydrogenate
H3C
H
H
O
C
C
C
H FAD
H
(CH2)n
SCoA Fatty acyl-CoA
acyl-CoA dehydrogenase FADH2
H3C
(CH2)n
C H
H
O
C
C
SCoA
trans-¦¤2-enoyl-CoA 45
Step 2. Hydration H3C
(CH2)n
C
H
O
C
C
Trans-¦¤2-enoyl-CoA
H H2O
H3C
(CH2)n
SCoA
enoyl-CoA Hydratase
OH H
O
C
C
C
H
H
3-L-Hydroxyacyl-CoA
SCoA
46
Step 3. Dehydrogenate
H3 C
OH H
O
C
C
C
H NAD+
H
3-L-Hydroxyacyl-CoA
(CH2)n
NADH + H+
hydroxyacyl-CoA dehydrogenase
O H3 C
(CH2)n
C
SCoA
O CH2
C
SCoA
β-Ketoacyl-CoA 47
Step 4. Thiolytic cleavage O H 3C
(CH2)n
C
O CH2
C
SCoA
β-Ketoacyl-CoA HSCoA
β-Ketothiolase
O H3 C
(CH2)n
C
O SCoA + CH3
Fatty acyl-CoA (2C shorter)
C
SCoA
Acetyl-CoA 48
The β-oxidation pathway is cyclic
49
Summary one cycle of the β-oxidation:
fatty acyl-CoA + FAD + NAD+ + HS-CoA →fatty acyl-CoA (2 C less) + FADH2 +
NADH + H+ + acetyl-CoA
50
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. 51
-Oxidation of Myristic(C14) Acid
52
-Oxidation of Myristic (C14) Acid
6 cycles
7 Acetyl CoA
53
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 Cycles Fatty Acid (C/2) (C/2 –1) 12 6 5 14 7 6 16 8 7 18 9 8 54
ATP for Myristic Acid C14 ATP production for Myristic(14 carbons): Activation of myristic acid 7 Acetyl CoA 7 acetyl CoA x 12 ATP/acetyl CoA 6 Oxidation cycles 6 NADH x 3ATP/NADH 6 FADH2 x 2ATP/FADH2 Total
-2 ATP 84 ATP 18 ATP 12 ATP 102 ATP 55
Oxidation of Special Cases (monounsaturated fatty acids)
56
Odd Carbon Fatty Acids(13C) CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA
TCA Cycle
CO2H Mutase
CH3-C-H
HO 2CCH2CH2COSCoA
Succinyl CoA
Epimerase
Vit. B12
COSCoA L-Methylmalonyl CoA
Propionyl CoA Carboxylase ATP/CO2
CO2 H H-C-CH3 COSCoA
D-Methylmalonyl CoA
57
O CH3 CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 2 ATP
C
OH
O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
CoA
C
FADH2
O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
OH CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH
O CH2
O
NADH
CoA
C
CoA
C O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH CH2
CoA
C
O
O CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH
CoA
CH2
C
CoA 58
SUMMARY OF ENERGY YIELD ENERGY YIELD
ATP EQUIVALENT
OXIDATION
FADH2
2 ATPs
OXIDATION
NADH
3 ATPs
CITRIC ACID CYCLE
Acetyl CoA
12 ATPs
PROCESS
ACTIVATION
ATP USED
2
59
SUMMARY OF ENERGY YIELD Lauric acid (C12) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
5 FADH2
10 ATPs
OXIDATION
5 NADH
15 ATPs
CITRIC ACID CYCLE
6 Acetyl CoA
72 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
95 ATPs
60
PALMITIC ACID (16 C) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
7 FADH2
14 ATPs
OXIDATION
7 NADH
21 ATPs
CITRIC ACID CYCLE
8 Acetyl CoA
96 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
129 ATPs 61
STEARIC ACID (18 C) ENERGY YIELD
ATP EQUIVALENT
OXIDATION
8 FADH2
16 ATPs
OXIDATION
8 NADH
24 ATPs
CITRIC ACID CYCLE
9 Acetyl CoA
108 ATPs
PROCESS
ACTIVATION
ATP USED 2
TOTAL
146 ATPs 62
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.
63
R - CH 2 - CH - CH2 - COOH
[O] Hydroxylase
CH 3
R - CH2 - CH - CH - COOH CH 3 OH -hydroxyadd Dehydrogenase
R - CH 2 - CH - COOH
CO2
CH3 Lower chain F.A. -Oxidation
[O]
2H
R - CH2 - CH - C - COOH Oxidative CH 3 O decarboxylation -keto acid
Propionyl ~ CoA + Acyl ~ CoA
-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. 64
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
HOOC - CH2
CH2 COOH -Oxidation CH2 Dicarboxylicacid COOH Repeated -Oxidation (Aoetyl- CoA)
HOOC - (CH2)4 - COOH Adipicacid HOOC - (CH2)6 - COOH Subericacid
65
66
Ketone Bodies
67
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.
68
Types
123-
69
The formation of ketone bodies (Ketogenesis) Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase
70
71
Utilization of ketone bodies (ketolysis) Occurs at extrahepatic tissues Succinyl-CoA transsulfurase
72
HSCoA ATP -
AMP PPi
Acetoacetate thiokinase
Occurs at extrahepatic tissues due to Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver. 73
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 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 74
Hepatocyte
Acetoacetate, β-hydroxybutyrate, acetone Ketone body formation Fatty Acetyl-CoA acids β-oxidation CoA
Citric Acid cycle
Ketone bodies exported as energy source for heart, skeletal muscle, kidney, and brain
oxaloacetate gluconeogenesis Glucose
Glucose exported as fuel for tissues such as brain 75
Ketosis consists of ketonemia, ketonuria and smell of acetone in breath 76
Causes for ketosis • Severe diabetes mellitus
• Starvation • Hyperemesis (vomiting) in early pregnancy
77
Metabolic Acidosis in Untreated Diabetes Mellitus CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid
OH CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid
Concentration of acetoacetic acid can result in metabolic acidosis affinity of Hb for O2 coma death 78
Lipogenesis
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:
80 80
2- Synthesis of glycerol-3- phosphate:
81
3-Formation of TAG
82
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
83 83
Fatty Acid Biosynthesis
84
1. Cytoplasmic or extramitochonderial (de novo)
synthesis 2. Microsomal pathway (aerobic elongation pathway & ∆9 Unsaturation)
3. Mitochondrial (anaerobic elongation ) 85
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
86
Reactivity of acetyl Coenzyme A Nucleophilic acyl substitution O
CH3CSCoA
HY ••
O
CH3C
Y •• + HSCoA
Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent) 87
88
Reactivity of acetyl Coenzyme A can react via enol O
OH H2C
CH3CSCoA
CSCoA E+
Acetyl coenzyme A reacts with biological electrophiles at its α carbon atom E
O CH2CSCoA
89
Citrate Shuttle Or Citrate-pyruvate cycle
Glycolysis
Citrate synthease
ATP-Citrate lyase
Pyruvate carboxylase Malic enzyme
+ CO2 90
The sources of NADPH are as follows: 1-Pentose phosphate pathway 3- Cytoplasmic isocitrate dehydrogenase 3-Malic enzyme
91
Process of synthesis: (1) Formation of Malonyl Coenzyme A (Carboxylation of Acetyl CoA) (2) Repetitive steps catalyzed by fatty acid synthase
92
(1) Carboxylation of Acetyl CoA O CH3 C SCoA + HCO3 acetyl-CoA
ATP
ADP + Pi biotin
acetyl-CoA carboxylase
O OOC CH2 C SCoA malonyl-CoA
Malonyl-CoA serves as the donor of twocarbon unit. 93
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.
94
glucagon ATP
insulin ADP + Pi
acetyl-CoA + HCO3 + H+ malonyl-CoA acetyl-CoA carboxylase (biotin) long chain acyl-CoA citrate isocitrate
95
Regulation of Fatty Acid Synthesis • Regulation of Acetyl carboxylase – Global （+） insulin （-） glucagon （-） epinephrine
– Local （+）Citrate （-） Palmitoyl–CoA （-） AMP 96
(2) Repetitive steps catalyzed by fatty acid synthase Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are: in bacteria catalyzed by seven separate enzymes. in mammals catalyzed by individual domains of a single large polypeptide. 97
98
Fatty acid synthase complex (multifunctional enzyme) • • • • • • • •
Acyl carrier protein (A) Acetyl-CoA-A transacetylase (AT) β-Ketoacyl-A synthase (KS) Malonyl-CoA-A transferase (MT) β-Ketoacyl-A reductase (KR) β-Hydroacyl-A dehydratase (HD) Enoyl-A reductase (ER) Thioesterase (TE)
99
AT
MT HD
Cys Subunit division
HS HS
KR A
Functional division
KS
ER
TE PhP HS HS
PhP
Cys
TE KS
A KR
ER
HD
MT
AT
A contains 4’-phosphopantotheine. 100
Fatty acid synthase complex
101
O
HS CH3 C S
CH 3 C S CoA O HS HS
A-HS KS-HS
OOC CH 2 C S CoA
O
HS CoA O
MT AT
HS CoA
OOC CH2 C S CH3 C S O
O CH3 (CH2)14 C O O
(After 7 rounds)
HS CH3 CH2 CH2 C S
TE
H2O
①
condensation KS CO 2
O O
CH3 C CH2 C S HS O
AT
CH3 CH2 CH2 C S HS
② ④
O
reduction NADP+
CH3 CH CH2 C S HS OH
ER
O NADPH + H+
CH3 CH CH C S HS
reduction
③
KR
NADPH + H+ NADP+
dehydration HD
102 H2O
The overall reaction of synthesis:
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+
palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O
103
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 A
Enzymes
Present as independent proteins
Multi-enzyme complex
Sequential units
2 carbon units split off 2 carbon units added, as 3 as acetyl CoA carbon malonyl CoA
Co-enzymes
NAD+ and FAD are reduced
NADPH used as reducing power 104
Routes of synthesis of other fatty acids
105
2. Elongation of palmitate Elongation beyond the 16-C length of the palmitate occurs in mitochondria and endoplasmic reticulum (ER).
106
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. 107
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
108
O 10 9
oleate 18:1 cis 9
C
OH
Desaturases introduce double bonds at specific positions in a fatty acid chain.
109
Orlistat: A Fatty Acid Synthase (FAS) Inhibitor Anti-obesity (Inhibits pancreatic lipase in GIT) Inhibits thioesterase domain of FAS Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis
110
Metabolism of phospholipids
Phospholipids • 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
112
• Phospholipid refers to phosphorouscontaining lipids. Glycerophospholipids Phospholipids Sphingolipids
113
Phospholipids
Sphingosine as alcohol
Glycerol as alcohol
Non nitogenous base
Nitrogenous base
Sphingomyeline
Phosphatidic acid
Cephalin
Cardiolipin 2phosphatidic acid Liked by glycerol
Lecithin
2nd
Lipositol messenger
Phosphatidyl serine
Lysophospholipid
Plasmalogen
114
Classification and Structure of Glycerophospholipids
• Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base.
115
glycerol
fatty acids
nitrogenous base
Phosphatidylcholine 116
甘油 glycerol 脂酰基
CH2 O
O R2
C
O
O
fatty acyl group
C CH2
H
C
R1
fatty acyl group 脂酰基
O O
P
Nitrogenous O X 含氮化合物 base
OH
The basic structure of glycerophospholipid 117
In general, glycerophospholipids contain a saturated fatty acid at C-1 and an unsaturated fatty acid (usually arachidonic acid) at C-2. 118
Some common glycerophospholipid
119
Some common glycerophospholipid (continue)
120
Synthesis of Glycerophospholipid Location: All tissue of body, especially liver & kidney Endoplasmic reticulum Pathways: 1- CDP-diacylglycerol pathway 2- Diacylglycerol pathway 121
The system of synthesis a. FA Glycerol
from carbohydrate
b. poly unsaturated fatty acid from plant oil c. choline ethanolamine serine inositol
from food or synthesis in body
d. ATP, CTP
e. Enzymes and cofactors 122
Diacylglycerol pathway CO2 HO CH2 CH COOH
HO CH2 CH2 NH2
3 SAM
HO CH2 CH2 N(CH3)3
Choline
Ethanolamine
NH2
Serine
ATP
ATP
ADP
ADP
P O CH2 CH2 N(CH3)3
P O CH2 CH2 NH2
Phosphocholine
Phosphoethanolamine CTP
CTP
PPi
PPi
CDP O CH2 CH2 NH2
CDP O CH2 CH2 N(CH3)3
CDP-choline
CDP-ethanolamine CO2
Phosphatidyl serine
DG
DG
CMP
CMP
Phosphatidyl ethanolamine
3 SAM
Phosphatidyl choline 123
CDP-Diacylglycerol pathway Dihydroxyacetone phosphate
Glycerol 3-phosphate
Phosphotidate CTP
G
PPi CDP-diacylglycerol Inositol CMP
Serine
Phosphatidyl glycerol CMP
CMP Phosphatidyl inositol
Diphosphatidyl glycerol (cardiolipin) Phosphatidyl serine 124
Degradation of glycerophospholipids by phospholipase Snake venom
A1 O A2 O R2
C
O
O
CH2 C CH2
C
R1 D
H
O O
P
O
X
OH C
125
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 126
Lysophospholipids, the products of Phospholipase A hydrolysis, are powerful detergents. O
O O R2
C
CH2 O
C
H
O C
R1 H2O
R2
P O
phospholipid
O
CH2
HO
O PLA2
CH2O
C
O
O X
C
O H
O
CH2O
P
C
R1
O X
O Lysophospholipid 127
Metabolism of sphingolipids • Palmitic acid + serine Called Sphingosine • Sphingosine + Fatty acid Called ceramide • Ceramide + Choline Called Sphingomylein
128
129
130
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 surrounding alveoli; decreases surface tension of fluid to prevent lung collapse Treatment in infants born before 30 weeks includes istration of artificial lung surfactant (e.g., Exosurf or
Pumactant)
131
Glycolipids
132
Ceramide + galactose Cerebroside Sulphate
Sulphatides
+ one or more of sialic acid (eg NANA or N acetyl galactos amine
Gangliosides
133
Synthesis of Gangliosides OH trans
CH3(CH2)12CH=CH-CH-CH-CH2OH CH3(CH2)nCONH
Ceramide
OH trans
CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar CH3(CH2)nCONH
Glucose or galactose
Cerebroside
Ceramide - Sugar - Sugar - GalNAc - Gal NAN = N-acetylneuraminate GalNAc = N-acetylgalactose
NAN
Ganglioside
134
Lipid Storage Diseases (Gangliosidoses)
135
Tay-Sachs Disease GM2 (a ganglioside): Ceramide - O - Glucose - Galactose - N-Acetylgalactose Hexoseaminidase A catalyzes cleavage of this glycoside linkage Autosomal recessive disorder characterized by deficiency of hexoseaminidase A; accumulation of gangliosides in brain Most prevalent in Jews from Eastern Europe For further information see: http://www.marchofdimes.com/professionals/681_1227.asp
136
Other Gangliosidoses Gaucher’s disease: Ceramide - O - Glucose -glucosidase Fabry’s disease: Ceramide - O - Glucose - O - Galactose - O - Galactose -galactosidase Nieman-Pick disease: Ceramide - Phosphate - Choline sphingomyelinase
137
Eicosanoid Hormones • 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
138
Eicosanoid Hormones
139
Cholesterol Metabolism
140
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. 141
2. Structure of cholesterol All steroids have cyclopentano penhydro phenanthrene ring system. H3C 21
22
18 CH3 12 19 CH3 1 2
HO
4
C
24
25
CH3
20
26
27 CH3
17 13
D 16
14
15
9 10
A
3
11
23
5
B 8 6
7 142
Cholesterol ester
O C
O
R 143
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 144
Acetyl-CoA is the direct and the only carbon source. 145
Acetyl-CoA HMG-CoA
Acetoacetyl-CoA
HMG CoA reductase is the rate-limiting enzyme 146
The total process of cholesterol de novo synthesis 147
Regulation of cholesterol synthesis
fasting
HMG CoA
Glucagon
HMG CoA reductase
after meal
insulin
MVA
thyroxine
cholesterol
bile acid
148
Transformation and excretion of cholesterol
Bile acids
Steroid hormones
Vitamin D Cholesterol
149
1. Conversion of Cholesterol into bile acid (1) Classification of bile acids The primary bile acids are synthesized in the liver from cholesterol. The 7hydroxylase is rate-limiting enzyme in the pathway for synthesis of the bile acids. 150
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.
151
Classification of bile acids Classification
Free bile acids
Cholic acid
Glycocholic acid
Taurocholic acid
Chenodeoxycholic acid
Glycochenodeoxycholic acid
Taurochenodeoxycholic acid
Deoxycholic acid
Glycodeoxycholic acid
Taurodeoxycholic acid
Lithocholic acid
Glycolithocholic acid
Taurolitho-cholic acid
Primary bile acids
Secondary bile acids
Conjugated bile acids
152
(2) Strcture of bile acids OH
COOH
COOH
12
3
HO
7
H cholic acid
OH
OH
HO
H
OH
glycocholic acid
HO
OH H chenodeoxycholic acid
CONHCH2COOH
HO
OH
H
CONHCH2CH2SO3H
OH
taurocholic acid
153
OH
HO
H deoxycholic acid
COOH
COOH
HO
H lithocholic acid
154
(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. 155
(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.
156
2. Conversion of cholesterol into steroid hormones • Tissues: adrenal cortex, gonads
• Steroid hormones: cortisol (glucocorticoid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol
157
Steroids derived from cholesterol
158
3. Conversion into 7-dehydrocholesterol
159
Esterification of cholesterol • in cells SHCoA acyl CoA O
HO
cholesterol
acyl CoA cholesterol R C O acyl transferase cholesteryl ester (ACAT)
160
in plasma
161
Plasma Lipoproteins
162
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
163
Structure
164
Types and Separation
165
Classification of plasma lipoproteins 1. electrophoresis method: - Lipoprotein
fast
pre -Lipoprotein -Lipoprotein CM (chylomicron)
slow
166
2. Ultra centrifugation method： high density lipoprotein (HDL) high low density lipoprotein ( LDL) very low density lipoprotein ( VLDL) CM (chylomicron ) low
167
Composition
168
electron microscope
169
CM
LDL
VLDL
HDL
－
＋
Origin
CM
Pre-
Separation of plasma lipoproteins by electrophoresis on agarose gel 170
§ 5.3 Structure
171
§ 5.4 Composition of lipoprotein CM
VLDL
LDL
HDL
<1.006
0.951.006
1.0061.063
1.0631.210
Protein
2
10
23
55
Phospholipids
9
18
20
24
Cholesterol
1
7
8
2
Cholesteryl esters
3
12
37
15
TG
85
50
10
4
Density(g/ml)
172
§ 5.5 Apolipoproteins
173
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. 174
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. 175
1. CM • Chylomicrons are formed in the intestinal mucosal cells and secreted into the lacteals of lymphatic system.
176
structure of CM
Apolipoproteins
phospholipids
Cholesterol
Triacylglycerols and cholesteryl esters
177
Metabolism of Chylomicrons
178
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 179
2. VLDL • Very low density lipoproteins (VLDL) are synthesized in the liver and produce a turbidity in plasma.
180
Metabolism of LDL and VLDL
181
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 182
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.
183
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
185
LDL receptors Cholesterol ester
protein
Cholesterol
LDL
Cholesteryl oleate
Amino acids LDL binding
Internalization
Lysosomal hydrolysis 186
Michael Brown and Joseph Goldstein were awarded Nobel prize in 1985 for their work on LDL receptors.
187
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.
188
4. HDL • LDL variety is called “ bad cholesterol” whereas HDL is known as “ good cholesterol” .
189
Liver
Heart VLDL
“Good” Excretion
“BAD” LDL Cholesterol Deposit
HDL
Forward and reverse cholesterol transport 190
Reverse cholesterol transport • Cholesterol from tissues reach liver, and is later excreted. This is called reverse cholesterol transport by HDL.
191
Metabolism of HDL
192
193
CETP • Cholesterol ester transfer protein (CETP) transfer cholesterol ester in HDL to VLDL and LDL.
194
Summary of HDL • Formation site: liver and intestine • Function: transport cholesterol from peripheral tissues to liver
195
summary of lipoprotein metabolism
196
Hyperlipidemias classification
Lipoprotein
Blood lipids
Ⅰ
CM
TAG↑ ↑ ↑ CH↑
Ⅱa
LDL
CH↑ ↑
Ⅱb
LDL, VLDL
CH↑ ↑ TAG↑ ↑
Ⅲ
IDL
CH↑ ↑ TAG↑ ↑
Ⅳ
VLDL
Ⅴ
VLDL, CM
TAG↑ ↑ TAG↑ ↑ ↑ CH↑ 197
Role of Ox LDL in plaque formation and atherosclerosis
198
199
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. 200
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 the201 plasma.
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). 202
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. 203
204
205
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