1
Lipids
and
lipoproteins
metabolism
2
Outline
1. Introduction
2. Digestion and absorption in GI
3. Formation and secretion of lipoproteins (chylomicron) by
enterocytes
4. Blood circulation and targeting of dietary lipids and
lipoproteins
5. Destination of fatty acids in tissues
6. Lipid transport in fed state
7. Lipid transport in fasted state
8. Oxidation of fatty acids
3
1. Importance of lipids and lipoproteins
•
•
•
•
•
•
•
Heterogeneous group of water insoluble organic molecules
Major source of energy (9Kc/1gr)
Storage of energy (TAG in adipose tissue)
Amphipatic barriers (PL, FC)
Regulatory or coenzyme role (vitamins)
Control of body’s homeostasis (steroid hormones, PG)
Consequences of imbalance in lipids and lipoproteins
metabolism:
– Atherosclerosis
– Obesity
– Diabetes
4
1. Importance of lipids and lipoproteins
Obesity
Atherosclerosis
5
Lipid metabolism
2. Digestion and absorption
of
Dietary fats
in
GI
6
2.1. Dietary fats contents
• Triacylglycerol (TAG)
– Over 93% of the fat that is consumed in the diet is
in the form of triglycerides (TG) or TAG
• Cholesterol (FC, CE)
• Phospholipids (PL)
• Free fatty acids (FFA)
7
2.2. Dietary sources of Lipids
• Animal Sources
• Vegetable Sources
8
General
schematic
9
2.3. Digestion of dietary fats
 Digestion in stomach
 Lingual lipase -----acid stable
 Gastric lipase -----acid stable
• These enzymes are most effective for short and medium chain
fatty acids
• Milk, egg yolk and fats containing short chain fatty acids are
suitable substrates for its action
• Play important role in lipid digestion in neonates
10
2.4.Digestion in small intestine
11
2.5. Bile Salts
 Bile salts are synthesized in the liver and stored in
the gallbladder
 They are derivatives of cholesterol
 Bile salts help in the emulsification of fats
 Bile salts help in combination of lipase with two
molecules of a small protein called as Colipase. This
combination enhances the lipase activity
12
2.6. Pancreatic enzymes in degradation of
dietary lipids
• Pancreatic Lipase (along with
colipase)
– Degradation of TAG
• Cholesteryl estrase
– Degradation of cholesteryl
esters
•
Phospholipase A2 and
lysophospholipase
- Degradation
of Phospholipids
13
2.6. Pancreatic enzyme
PLase A2
14
2.7. Control
of lipid digestion
 Cholecystokinin
 Secretin
 Bicarbonate
15
2.8. Disorders
1. Lithiasis
2. Cystic fibrosis
16
2.8. Disorders: Lipid Malabsorption
• Steatorrhea: increased lipid and fat soluble
vitamin excretion in feces.
– Possible causes of steatorrehea
• Colipase deficiency
17
3. Absorption and secretion of lipids by enterocytes
TAG: triacylglycerol
DAG: diacylglycerol
MAG: monoacylglycerol
FA: fatty acid
CL: cholesterol
BS: bile salt
LPA: lysophosphatidate
CE: cholestryl ester
ACAT: acyl-CoA cholesterol acyl transferase
CM: chylomicron
MTP: microsomal TAG transfer protein
AGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase
18
3. Secretion of lipids from enterocytes
 After a lipid rich meal, lymph is called chyle
19
4. Blood circulation and targeting of dietary
lipids and lipoproteins
20
4. Blood circulation and targeting of lipids and
lipoproteins
21
4.1. ApoC-II, lipoprotein lipase (LPL) ,
deficiency and heparan sulfate
Glycerol
(exogenous)
Chylomicron
remnant
Clearing
factor
LPL
Liver
HDL
22
6. Destination of fatty acids in tissues
• Muscle tissue and liver: Catabolism (oxidation)
– The end product of FAs catabolism (acetyl-CoA):
• as fuels for energy production (TCA)
• as substrates for cholesterol and ketone body synthesis
• Adipose tissue: Storage (TAG)
23
7. Lipids and lipopoteins transport in fed state
Small intestine
Dietary TAG
Blood
stream
liver
Glucose &
other fuels
Acetyl-CoA FAs
TAG
Chylomicron (TAGendo) and VLDL (TAGexo)
Adipose tissue
FAs
FAs
Muscle
energy
TAGs
24
8. Lipids and lipopoteins transport in long
Brain
fasted state
liver
Ketone bodies
FAs
Glucose
Acetyl-CoA
Acetyl-CoA
Glycerol
energy
Ketone
bodies
Blood
stream
ketone bodies
FAs-albumin glycerol
Adipose tissue
FAs+Glycerol
FAs(+ketone bodies)
Muscle
energy
TAGs
25
26
• Pathway for catabolism of saturated fatty
acids at the β carbon atom with successive
removal of two carbon atoms as acetyl CoA
• Site:
– Cytosol (activation)
– Mitochondria
• Membrane transport
• Matrix ( β oxidation)
27
9.1.1. Activation and transport of fatty acids
into mitochondria
Acyl CoA synthase
28
9.1.1. Entry of short and medium chain FA
into mitochondria
• Carnitine and CAT system not required for
fatty acids shorter than 12 carbon length.
• They are activated to their CoA form inside
mitochondrial matrix.
29
9.1.1.1. Carnitine deficiencies
• Primary causes:
– Carnitine acyl transferase-I (CAT-I) deficiency: mainly
affects liver
– Carnitine acyl transferase-II (CAT-II) deficiency:
mainly affects skeletal and cardiac muscles.
• Secondary causes :
– liver diseases: decreased endogenous synthesis
30
9.1.1.1. Consequence of carnitine
deficiencies
• Excessive lipid accumulation occurs in muscle, heart,
and liver
• Cardiac and skeletal myopathy
• Hepatomegaly
• Low blood glucose in fasted state hypoglycemia
coma
31
32
• Provision of energy
– Major pathway of acetyl-CoA
• Cholesterol production
• Ketone bodies production
– Diabetes
– Starvation
33
Types of fatty acyl CoA dehydrogenases
• Long chain fatty acyl CoA dehydrogenase (LCAD)
• Medium chain fatty acyl CoA dehydrogenase (MCAD)
• Short chain fatty acyl CoA dehydrogenase (SCAD)
MCAD deficiency is thought to be one of the most
common inborn errors of metabolism.
34
Muscle tissue and liver
The first level
Insulin
TAG
Glucagon Epinephrine
The second level
The third level
-
+
FFA
FFA
CAT
1
FFA
Acetyl-CoA
NADH
Adipose tissue
TCA
Malonyl-CoA
Acetyl-CoA and NADH inhibition of ᵦ oxidation enzymes
35
Peroxisomal FA oxidation
• Acts on very long chain fatty acids (VLCFAs)
• Zellweger syndrome
– Absence of peroxisomes
– Rare inherited disorder
– VLCFA cannot be oxidized
– Accumulation of VLCFA in brain, blood and other
tissues like liver and kidney
36
Omega oxidation
• It is a minor pathway
• Takes place in microsomes
• Involves oxidation of last carbon atom ( ω
carbon)
• More common with medium chain fatty acids
37
Alpha oxidation
• Seen in branched chain fatty acid, phytanic acid
• Occurs in endoplasmic reticulum
• Refsum disease
– Genetic disorder
– Caused by a deficiency of alpha hydroxylase
– There is accumulation of phytanic acid in the plasma
and tissues.
– The symptoms are mainly neurological.
38
Acetyl CoA and lipid metabolism
Mitochondria
Cytosol
GLC
Protein
Ketone bodies
HMG-CoA
TCA
FA
TAG & PL
Acetyl-CoA
HMG-CoA
TAG - Protein -Glucose
Cholesterol
Pentose phosphate
pathway
39
De Novo synthesis of fatty acids
• Saturated fatty acids are synthesized from
acetyl CoA
• Occurs in cytoplasm
• Occurs mainly in liver, adipose tissue and
lactating mammary gland
• Need to
– acetyl CoA
– NADPH
40
De Novo synthesis of fatty acids
• Phase I
– Transport of substrates into cytosol
– Carboxylation of acetyl-CoA to malonyl-CoA
• Phase II
– Utilization of substrate to form palmitate by fatty
acid synthase complex
• Phase III
– Elongation and desaturation of palmitate to
generate different fatty acids
41
Acetyl CoA activation and regulation of it
+
Glucagon and
epinephrine
42
Synthesis of palmitate by fatty acid
synthase(FAS)
43
Modification of dietary and
endogenous fatty acids
• Chain elongation to give longer fatty acids
• Desaturation, giving unsaturated fatty acids
44
Modification of dietary and
Essential fatty acids
endogenous fatty acids
ω-3
ω-6
ω-7
ω-9
45
TAG
formation
Glucose
Glycerol
ATP
ADP
NADH, H+ NAD+
Pyruvate
Dihydroxy acetone
phosphate
Acyl-CoA
CoA
Glycerol 3-P
Acyl-CoA
NADH, H+ NAD+
1acyl-dihydroxy
acetone phosphate
CoA
1acyl- glycerol
3-P
Acyl-CoA
CoA
1,2Diacyl- glycerol 3-P
(phosphatidate)
Pi
Monoacylglycerol
Acyl-CoA
CoA
46
Diacylglycerol
Acyl-CoA
CoA
TAG
Fates of TAG in liver and adipose tissue
• Adipose tissue: TAG stored in cytosol
• Liver: very little stored. Exported out of liver in VLDL ,
which exports endogenous lipids to peripheral
tissues
47
FFA
Lipolysis
48
Mobilization of stored fats and release of FAs
Glucagon &
epinephrine
+
P
P
P
P
P
P
HSL
HSL-P
49
Metabolism
of
cholesterol
50
Cholesterol
51
Cholesterol importance
•
•
•
•
•
Membrane component
Steroid synthesis
Bile acid/salt precursor
Vitamin D precursor
It is synthesized in many tissues from acetyl-CoA and
is eliminated from the body in the bile salts
52
Liver cholesterol pool
De novo synthesis
Diet
Cholesterol synthesized
in extrahepatic tissues
Liver cholesterol
pool
Secretion of HDL
and VLDL
Free cholesterol Conversion to bile salts/acid
In bile
53
Cholesterol Synthesis
• Occurs in cytosol
• Requires NADPH and ATP
• All carbons from acetyl-CoA
• Highly regulated
• Site : Liver, adrenal cortex, testis, ovaries And intestine.
• All nucleated cells can synthesize cholesterol.
• Area :The enzymes of synthesis are located partly in
endoplasmic reticulum and partly in cytoplasm.
54
Cholesterol
Synthesis
55
Regulation of Cholesterol synthesis
Covalent modification
56
Regulation of Cholesterol synthesis
• Regulation at transcription
57
Lipoprotein metabolism
58
Structure of lipoprotein
INTEGRAL APOPROTEINS
CHOLESTEROL
ESTERS
MONOLAYER OF
PHOSPHOLIPID
AND CHOLESTEROL
CORE
TRIGLYCERIDES
PERIPHERAL APOPROTEIN
59
Apoproteins
A
A-I Liver& intestine
A-II
Liver
B
B-48
B-100
Intestine
Liver
C
E
C-l
C-ll
C-lll
Liver
All Liver
60
Classification
Based on density by ultracentrifugation
i.
ii.
iii.
iv.
v.
Chylomicrons
Very Low Density Lipoprotein
Intermediate Density Lipoprotein
Low Density Lipoprotein
High Density Lipoprotein
61
Composition and size of lipoprotein
62
Lipoprotein function
63
Exogenous cycle(Metabolism of CM)
64
Endogenous cycle(VLDL)
65
HDL- cholestrol metabolism
reverse cholesterol transport and
LDL metabolism
66
• Regulated: by LDL receptor
• Unregulated : by scavenger receptor(SR)
67
Regulated: by LDL receptor
68
regulated
LDL uptake by
LDL receptor
69
Unregulated LDL uptake by scavenger receptor
Antioxidants
-
+
Free radicals
Scavenger receptor
Atherosclerosis
70
Atherosclerosis
• Atherosclerosis is a form of arteriosclerosis in which
thickening and hardening of the vessel are caused by
the accumulation of lipid-laden macrophages or foam
cell within the arterial wall, which leads to the formation
of a lesion called a plaque
• Atherosclerosis is not a single disease
• It is the leading contributor to coronary artery and
cerebrovascular disease
71
Atherosclerosis
72
Hypercholesterolemia
• Normal serum cholesterol level 150-200mg/dl
• Increased cholesterol level is seen in following
conditions diabets mellitus, lipid nephrosis,
hypothyroidism
• Atherosclerosis
• Xanthomas (deposition of cholesterol in
subcutaneous tissue)
• Corneal arcus (deposits of lipid in cornea)
73
Fredrickson classification of the hyperlipidemias
74
Degradation of Cholesterol
• Synthesis of bile acids  Excretion in the
feces
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76
Cholesterol-lowering drugs
•
•
•
•
•
Statins
Fibric acid derivatives
Niacin
Bile-acid resins
Cholesterol absorption inhibitors
77
Ketone bodies
78
Ketone bodies
• Ketone bodies are metabolic products that are
produced in excess during excessive
breakdown of fatty acids
Acetone
βhydroxybutyrate
Acetoacetate
79
Ketone bodies importance
• Alternate sources to glucose for energy
• Production of ketone bodies under conditions
of cellular energy deprivation
• Utilization of ketone bodies by the brain
80
ketone bodies production and utilization
HMG-CoA synthase
81
• By availability of acetyl CoA
• Level 1
– Lipolysis
• Level 2
– Entry of fatty acid to mitochondria
• Level 3
– Oxidation of acetyl CoA
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Diabetic Ketoacidosis
With each ketone body, one
hydrogen atom is released in
bloodlowering of pH Acidosis.
84
Metabolism of complex lipids
Phospholipids
•
•
•
•
•
Polar, ionic compounds
alcohol
Phosphodiester bridge
Diacylglycerol or Sphingosine
Types:
– Glycerophospholipids
– Sphingophospholipids (sphingosine)
85
Synthesis of phospholipids
• Synthesized in smooth endoplasmic reticulum.
• Transferred to Golgi apparatus
• Move to membranes of organelles or to the
plasma membrane or released out via
exocytosis
• All cells except mature erythrocytes can
synthesize phospholipids
86
Synthesis of Glycerophospholipids
• Biosynthesis of anionic Glycerophospholipids
– Phosphatidylglycerol(PG)
– Phosphatidylinositol(PI)
– Cardiolipin
• Biosynthesis of neutral glycerophospholipids
– Phosphatidylcholine(PC)
– Phosphatidylethanolamine(PE)
•
87
Synthesis of Glycerophospholipids
• First strategy:
• biosynthesis of anionic Glycerophospholipids
– CTP:phosphatidate citidyl transferase:
R1
R2
R1
CTP PPi
R2
OP
Phosphatidate
Alcohol CMP
R1
R2
CDP
CDP-DAG
phosphoalcohol
Phosphatidyl alcohol
88
Synthesis of Glycerophospholipids
• Second strategy:
• Biosynthesis of neutral glycerophospholipids
– CTP:phospho alcohol citidyl transferase:
Alcohol
Phosphoalcohol
CDP-alcohol
CMP
R1
R2
R1
R2
OH
DAG
phosphoalcohol
Phosphatidyl alcohol
89
Sphingophospholipids
90
Sphingomyelin synthesis
• Ceramide is required for sphingomyelin synthesis
PC
DAG
91
Degradation of glycerophospholipids
• Phospholipases remove one fatty acid from C1 or C2
and form lysophosphoglyceride.
• Lysophospholipases act upon lysophosphoglycerides.
–
–
–
–
Phospholipase A1
Phospholipase A2
Phospholipase C
Phospholipase D
92
Phospholipases
Phospholipse
Product
Significant
A1
FA--- 1-lysophospholipid
Phospholipid transformation
A2
FA--- 2-lysophospholipid
Phospholipid transformation,
Eicosanoid synthesis
B
FA---- Glycerol 3-phosphoalcohol
Lysophospholipid
degradation
C
Phosphoalcohol---1,2DAG
Secondary messenger
production
D
Alcohol---- phosphatidic acid
Secondary messenger
production
93
Degradation of Sphingomyelin
• Sphingomyelinase
• Ceramidase
• Sphingosine and ceramide act as intracellular
messengers.
94
Glycolipids
• Carbohydrate and lipid components
• Derivatives of ceramide
• Essential components of all membranes,
greatest amount in nerve tissue
• Interact with the extracellular environment
• No phospholipid but oligo or mono-saccharide
attached to ceramide by O-glycosidic bond.
95
Classes of Glycosphingolipids
• Neutral glycosphingolipids :
– Cerebrosides
– Globosides
• Acidic glycosphingolipids:
– Ganglioside
– Sulfatides
96
Synthesis of Neutral Glycosphingolipids
• Site:
– Golgi apparatus
• Subtrates
– Ceramide, sugar activated by UDP
• Galactocerobrosides
– Ceramide + UDP- galactose
• Glucocerebrosides
– Ceramide + UDP – glucose
• Enzymes
– Glycosyl transferases
97
Synthesis of Acidic Glycosphingolipids
• Gangliosides
– ceramide + two or more UDP- sugars react
together to form Globoside.
– NANA combines with globoside to form
Ganglioside.
98
Synthesis of Acidic Glycosphingolipids
• Sulfatides
– galactocerebroside gets a sulphate group from a
sulphate carrier with the help of sulfotransferase
and forms a sulfatide.
99
Degradation of glycosphingolipids
• Done by lysosomal enzymes
• Different enzymes act on specific bonds
hydrolytically ---- the groups added last are
acted first.
100
Sphingolipidoses
•
•
•
•
Lipid storage diseases
Accumulation of sphingolipids in lysosomes
Partial or total absence of a specific hydrolase
Autosomal recessive disorders
101
Degradation of glycosphingolipids
102
Eicosanoids- Classification
Eicosanoids are classified in to two main groups1) Prostanoids
2) Leukotrienes and Lipoxins
Prostanoids are further sub classified in to three groupsa) Prostaglandins(PGs)
b) Prostacyclins(PGIs)
c) Thromboxanes (TXs)
103
Characteristic features of prostaglandins
1)
2)
3)
4)
Act as local hormones
Show the autocrine and Paracrine effects
Are not stored in the body
Have a very short life span and are destroyed within
seconds or few minutes
5) Production increases or decreases in response to
diverse stimuli or drugs
6) Are very potent in action. Even in minute (ng
concentration), biological effects are observed.
104
Synthesis of eicosanoids
• Linoleic acid is the dietary precursor of PGs.
• Arachidonic acid is formed by elongation and
desaturation of linoleic acid.
• Membrane bound phospholipids contain
arachidonic acid.
• Phospholipase A2 causes the release of
arachidonic acid from membrane
phospholipids.
105
Synthesis of eicosanoids
NSAIDs
Steroidic antiinflammation drugs
106