LIPIDS METABOLISM

dr. I Wayan Surudarma, M.Si.

 LIPIDS
• Water-insoluble substances that can be
extracted from cells by nonpolar organic
solvents
– Triglycerides and fatty acids.
– Cholesterol
– Phospholipids
– Lipoproteins
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 Triglyceride
Triglycerides（triacylglycerols, TAG）
- made of 3 free fatty acids and 1 glycerol
- FFA 4-22 Carbons long (mostly 16-20)
- 95% of dietary lipids (fats & oils)

Glycerol + 3 FFA TAG + H2O

 Fatty Acids
• According to the number of carbon atom:
 short chain (2~4 C), medium chain (6~10 C) &
long chain (12~20 C) fatty acid
• According to whether it contains double bond or
not
 Saturated (have only single bonds)
 Unsaturated (have double bonds)
• According to the source
 Essential, non essential
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 Metabolism of Fat

1. Catabolism of TAG
– Lipolysis
– Fatty acid beta oxidation
– Ketogenesis and Ketone Bodies
2. Lipogenesis: Fatty Acid Synthesis
3. Synthesis of TAG
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Catabolism of Fat

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 LIPOLYSIS

Mobilization of triacylglycerols:
 In the adipose tissue
 Breaks down triacylglycerols to free fatty acids and
glycerol
 Fatty acids are hydrolyzed initially from C1 or C3 of
the fat
 Hormone sensitive lipase cleave a fatty acid from a
triglyceride, and fatty acid are released into the blood
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 CAPILLARY
lipoproteins
FABP MITOCHONDRION
LPL FA
2 acetyl-CoA TCA
A cycle 7
3 4
FA FA C -oxidation
S 6
albumin FA FA acyl-CoA acyl-CoA
FA FABP FABP 5
carnitine
1 CYTOPLASM transporter
From fat cell
FA = fatty acid
LPL = lipoprotein lipase
cell membrane FABP = fatty acid binding protein
ACS = acyl CoA synthetase

Overview of fatty acid catabolism

 Steps in FA Oxidation
• Fatty Acid Activation by esterification with CoASH
• Membrane Transport of Fatty Acyl CoA
• Carbon Backbone Reaction Sequence (Beta
Oxidation)
1. Dehydrogenation
2. Hydration
3. Dehydrogenation
4. Thiolase Reaction (Carbon-Carbon Cleavage)
 Activation of Fatty Acids
• Acyl CoA Synthetase reaction occurs on the
mitochondrial membrane
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Fatty acid Beta oxidation

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Fatty Acid Synthesis
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Regulation of Fatty Acid Synthesis
• Regulation of Acetyl carboxylase
• Global
（+） insulin
（-） glucagon
（-） epinephrine
• Local
（+）Citrate
（-） Palmitoyl–CoA
（-） AMP
-oxidation vs Fatty Acid Synthesis
 The Synthesis of TAG
Mono-acylglycerol pathway (MAG pathway)
(for dietary fat digestion and absorption)
pancreatic pancreatic
CH 2OCOR CH 2OCOR CH 2OH
lipase lipase
CHOCOR CHOCOR CHOCOR

CH 2OCOR CH 2OH CH 2OH

TAG FA DAG FA MAG

intestinal lumen

FA FA
ATP,CoA
acyl CoA acyl CoA CH 2OH

CHOCOR

CH 2OH
MAG
CH 2OCOR

CHOCOR
intestinal epithelium
CH 2OCOR
TAG

lymphatic vessels
Chylomicrons adipose tissue
 Diacylglycerol pathway (DAG pathway)
(for TAG synthesis of in adipose tissue, liver and kidney)
liver
kidney CH2OH
liver CH 2OH NADH+H + NAD+ CH2OH ADP ATP
adipose tissue CHOH
glucose CO
phosphoglycerol
CHOH
glycerol kinase CH2OH
CH 2O-PO 3H2 dehydrogenase CH 2O-PO 3H2
dihydroxyacetone glycerol
3-phosphoglycerol
phosphate
RCO¡« SCoA
acyl CoA transferase
HSCoA

HSCoA RCO¡« SCoACH2OCOR CH 2OCOR

CH2OCOR
CH 2OCOR HSCoA RCO¡« SCoA
Pi H2O CHOH
CHOCOR CHOCOR
CHOCOR
CH 2O-PO 3H2
acyl CoA CH2OH phosphatase CH2O-PO 3H2 acyl CoA
CH2OCOR lysophosphatidate
transferase diacylglycerol phosphatidate transferase
triacylglycerol
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Lipoprotein Metabolism
Lipoproteins
 Lipid compounds are transported in plasma as
Lipoproteins
For triacylglycerol transport (TG-rich):
• Chylomicrons: lipids of dietary origin (exogenous)
• VLDL: lipids of endogenous (hepatic) synthesis

For cholesterol transport (cholesterol-rich):

• LDL
• HDL

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 Classification of plasma lipoproteins
They are classified based on their density:
 Chylomicron (CM) (largest; lowest in density due to high
lipid/protein ratio; highest % weight triacylglycerols)
 VLDL (very low density lipoprotein; 2nd highest in
triacylglycerols as % of weight)
 IDL (intermediate density lipoprotein)
 LDL (low density lipoprotein, highest in cholesteryl esters
as % of weight)
 HDL (high density lipoprotein; highest in density due to
high protein/lipid ratio)

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 Lipoprotein classes
Lipo- Protein/lipid %
protein Source Apo Proteins Main lipid component Diameter(nm) Function
(A I,II,III,IV) 1/99 % 90-1000 Dietary:
CM Intest. (B48) TG FFA  Adipose/muscle
(C I,II,III) CE  Liver via
(E) remnants
CM CM (B48) 6/94 45-150
remnants (E) TG, PL, C
(B100) 7/93 30-90 Synthesized:
VLDL liver (CI,II,III) TG FFA adipose/muscle
CE  LDL
IDL VLDL (B100) 11/89 25-35
(E) TG, cholesterol
LDL Blood B100 21/79 20-25 CE to liver (70%) and
(VLDL) cholesterol peripheral cells (30%)
(A1,II,IV) PL, cholesterol HDL1: 20-25 supplies apo CII, E to
HDL Liver, (CI,II,III) HDL1: 32/68 (only apo-E) chylomicrons and VLDL;
1,2,3 intes., (D in HDL2,3) HDL2: 33/67 HDL2: 10-20 mediates reverse
VLDL, (E) HDL3: 57/43 HDL3: 5-10 cholesterol transport
CM preβHDL: 70/30 preβHDL:<5
Albumin/ Adipose Free fatty acids
FFA tissue 99/1
 Lipoproteins structure
The structure of lipoprotein is:

Central core formed of non-polar

lipids:
1. triacylglycerols (TG; TAG)
2. cholesterol esters (CE).

Outer layer contains polar lipids:

1. phospholipids (PL).
2. non-esterified cholesterol.
3. proteins (apoproteins).
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Hydrophobic lipids

Amphiphilic lipids

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 Important enzymes and proteins
involved in lipoprotein metabolism

• Enzymes (LPL, HL, LCAT, CETP).

• Apolipoproteins.
 Functions of apolipoproteins:
• Structural and transport function
• Enzymatic function
• Ligands for receptors
• Receptors
– LDL receptor  ApoB100, ApoE
– LDL receptor-related protein (LRP)  ApoB48.
– Scavenger receptor B1 (SRB1)  ApoA1 HDL
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 The Function of Apoproteins
Effect on enzyme
Apoprotein Structural function Receptor
activity

scavenger
receptor
AI HDL B1 (SRB1) LCAT activator
putative
HDL receptor

AII HDL HDL receptor? LCAT cofactor

probably
Plasminogen
(a) lp(a) interfereswith
receptor?
fibrinolysis

B48 chylomicrons LRP HTGL?

B100 VLDL, IDL, LDL LDL receptor -

CI, CII - - LPL activation 43

 Metabolism of Chylomicrons
1. Nascent chylomicrons are formed in the intestinal mucosa and
pass to the chyle and then to the blood stream through the
thoracic duct.
2. Apo-A and apo-B48 are Apoprotein component of the nascent
cylomicrons.
3. After entering the blood stream, the chylomicron particles transfer
apo-A to HDL and acquire apo-CII from HDL.
4. Apo-CII activates lipoprotein lipase LPL hydrolyze triglyceride (TG)
in the core of CM to free fatty acids and glycerol.
5. The fatty acids are released and oxidized in muscles or stored as
triglycerides in adipose tissue.
6. Formation of chylomicron remnants
7. CM remnants are taken up by liver cells due to apoE recognition
sites.
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 Metabolism of chylomicron

HDL

apo-E receptor

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 Metabolism of VLDLs
• Assembled and secreted by liver directly into blood.
• Carry lipids from liver to peripheral tissues.
• Mature VLDLs: contain Apo B-100 plus Apo C-II and Apo E.
• Lipoprotein lipase is required to degrade TG into glycerol and
fatty acids.
• As TG is degraded, VLDLs become
 Smaller in size
 More dense
 Apo C back to HDL

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 Metabolism of VLDL and LDL

70%
HDL

30%

LDL-receptor
apo-B/E receptor
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 LDL Receptor
• Also named as apoB-100/apoE receptors because of
its ability to recognize particles containing both apo
B and E (apo E>> apo B-100)
• LDL receptors exist in the liver and in most
peripheral tissues
• The complexes of LDL and receptor are taken into
the cells by endocytosis, where LDL is degraded but
the receptors are recycled

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 Summary of CM, VLDL, LDL
Chylomicron VLDL LDL
• Synthesized in • Synthesized in liver. • Synthesized from
small intestine • Transport IDL.
• Transport dietary endogenous TG. • Cholesterol
lipids • 90% lipid, 10% transport.
• 98% lipid, large protein.
• 78% lipid, 58%
sized, lowest density • Apo B-100 cholesterol & CE.
• Apo B-48: Receptor • Receptor
binding
• Apo B-100
binding
• Apo C-II: • Apo C-II • Receptor
Lipoprotein lipase • LPL activator binding
activator • Apo E
• Apo E: Remnant • Remnant
receptor binding receptor
binding
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 HDL
• These are the smallest and the most dense lipoprotein
particles.
• They contain large amount of proteins (50-60%) and very
little TG, while the predominant lipid is phospholipid.
• Synthesized de novo in the liver and small intestine,
primarily as protein-rich disc-shaped particles.
• Apo C- & E- are synthesized in liver and transferred from
liver HDL to intestinal HDL when enter the plasma.
• ApoA-I is synthesized by liver & intestine, which is secreted
in a lipid-poor form and then immediately recruits additional
PLs and free cholesterol (C) via the ABCA1 pathway, forming
nascent HDL.
 HDL Synthesis
• Nascent HDL consists of discoid PL bilayers containing apo E,
Apo C & free cholesterol (C).
• On entering the circulation:
 apo-A1, the major HDL apoprotein is acquired from CM
 apo-C is transferred to CM and VLDL.
• LCAT and its activator apo-A1, bind to the discoidal particles,
and the surface PL & free C are converted to CE &
lysolecithin.
• The non-polar CE move into the hydrophobic interior of the
bilayer, whereas lysolecithin is transferred to plasma albumin
 a spherical HDL is formed.
 HDL Metabolism
Apo-A
CM
Liver VLDL
Apo-C
Apo-E
Bile acids
LCAT Nascent HDL

C + FA C

Peripheral tissue
Apo-A
CE C
CE
C
LCAT
HDL receptor
Other lipoproteins
Mature HDL
HDL Metabolism
 LCAT (lecithin – cholesterol acyl transferase)

• Apo-AI activates LCAT which is present on the HDL surface.

– Free cholesterol, present on the HDL surface is esterified
by LCAT.

Formation of cholesterol esters in lipoprotein

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 Class B scavenger receptor B1 (SR-B1)

• In liver and in steroidogenic tissues: it binds HDL via

apo-A1, then CE is selectively delivered to the cells.
• In the tissues : SR-B1 mediates the acceptance of
cholesterol effluxed from the cells by HDL, which
then transports it to the liver for excretion.
 ATP-binding Cassette Transporters

• It involves the ATP-binding cassette transporters A1 & G1

(ABCA1 & ABCG1).
• They are transporter proteins that couple hydrolysis of ATP to
the binding of a substrate, enabling it to be transported
across the membrane.
• ABCG1: transports C from cells to HDL.
• ABCA1: preferentially promotes efflux to poorly lipidated
particles such as preβ-HDL, which are then converted to
discoidal HDL then to HDL3 and finally to HDL2.
 Functions of HDL
Function:
• Transports C from peripheral tissues to liver (reverse
C transport).
 Only HDL can pick up cholesterol from peripheral tissues

• HDL acts as a circulating store for apo-C & E

required in the metabolism of CM & VLDL.
THANK YOU