METABOLISME LIPID

Siufui
F. Ferdinal

BAGIAN BIOKIMIA dan BIOLOGI MOLEKULER

FAKULTAS KEDOKTERAN UNIVERSITAS
TARUMANAGARA
Jakarta, Oktober 2012
Definisi Lipid
• Kelompok senyawa yang secara kimia heterogen, akan
tetapi secara fisika memiliki satu sifat bersama, yaitu
relatif tidak larut dalam air dan larut dalam pelarut polar
(organik), seperti etanol, kloroform, eter, dll.

Fungsi Lipid
• Komponen struktur biomembran: fosfolipid kolesterol
• Simpanan enerji :TAG
• Regulator metabolik: hormon steroid, Eicosanoids
• Cellular recognition: Gangliosida
• Membantu absorpsi Fat Soluble vitamins
• Proteksi organ interna
• Thermal & Electric insulator
• Shape & Contour body
• Taste & Palatabllity
Klasifikasi Lipid
I. Simple Lipids, ester dari FA dengan berbagai alkohol
1. TAG (fats) – ester dari FA dengan gliserol
2. Waxes – ester dari FA dg monohidric alcohol chain

II. Complex Lipids, mengandung: FA, alkohol, fosfat, NB

1. Fosfolipid: Gliserofosfolipid: PC, PE, PS, PI
Sfingofosfolipid: Sfingomielin, Ceramide

2. Glikolipid : Cerebroside: mengandung satu residu

monosakarida.
Gangliosida: mengandung oligosakarida.
3. Other complex lipids:Sulfolipid,aminolipid, Lipoprotein

III. Precursor & Derived Lipids: FA. Glycerol, Steroids, Lipid-

soluble Vit, Eicosanoids, KB.
Asam Lemak ( Fatty Acid)
• Derivat asam karboksilat dari rantai panjang hidrokarbon
• Biasa dalam bentuk ester, ex: TAG
• Umumnya C12 – C26 (genap)
• Saturated FA – tanpa ikatan rangkap:ex: Palmitic acid
Unsaturated – dengan ikatan rangkap ( cis atau trans ):
- Mono unsaturated , ex: Oleic acid
- Poly unsaturated, ex: Linoleic, linolenic, arachidonic
TATANAMA
• Saturated FA : ber-akhiran anoic, ex; Hexadecanoic acid
• Unsaturated : berakhiran enoic, ex: Eicosatetraenoic acid
Numbering
Mulai dari atom C karboksil sebagai nomor 1, selanjutnya
2, 3, 4 etc atau α, β, γ, δ, etc, tetapi atom C terminal
disebut sebagai atom C ω (omega)
• Short chain FA 2 - 4 atom C
• Medium chain FA 6 – 10 atom C
• Long chain FA 12 – 24 atom C
• Palmitic acid 16:0
• Oleic acid 18:1; 9
• Arachidonic acid 20:4; 5, 8, 11, 14

W Series: posisi ikatan rangkap dari ujung W

Omega 3 – Linolenic acid ( 18:3; 9, 12, 15 ) atau
18:3 Δ 9,12,15
CH3 C C=C C C=C C C=C C C C C C C C COOH

Omega 6 – Linoleic acid ( 18:2; 9,12 ) atau 18:2 Δ 9,12

CH3 C C C C C=C C C=C C C C C C C C COOH

Omega 9 – Oleic acid ( 18:1;9 )

CH3 C C C C C C C C=C C C C C C C C COOH
Common Saturated Fatty Acids
Unsaturated Fatty Acids
Essential FA (EFA)
PUFA - Linoleic acid: walnut, wheat germ oil, canola oil,
fish liver oil, human milk, ogan
meats, seafood / fatty fish.
Linolenic acid: plant oils: corn, peanut, soybean,
cotton seed oils.
Arachidonic acid : dihasilkan dari Linoleic acid.

Fungsi EFA
• Pembentukan membran sel
• Perkembangan otak dan sistem saraf
• Sintesis Eicosanoids: Pg, Tx, Lt, dengan efek a.l:
- regulasi tekanan & visositas darah
- vasokonstriksi
- respon immun
- reaksi radang
Biochemical basis
• Manusia tidak memiliki enzim yang dapat memasukkan
ikatan rangkap pada posisi setelah atom C9-C10,
selama sintesis asam lemak.

Fungsi Spesifik EFA

• Struktur dan fungsi membran sel
• Transport kolesterol
• Pembentukan liporotein
• Mencegah Fatty Liver
Cis - Trans Fatty Acids
Fatty Acid Metabolism
Degradation and Synthesis
Dietary Lipids
Are Digested
by Pancreatic
Lipases
Dietary Lipids Are Transported in Chylomicrons
Fatty acids have four major physiological roles

1. FA are fuel molecules, primary source of energy (TAG)

2. Building blocks of phospholipids and glycolipid

3. Many proteins are modified by the covalent attachment

of fatty acids, which targets them to membrane
locations (Glycosyl phosphatidylinositol (GPI) anchor
or membrane anchor protein ).

4. FA derivatives serve as hormones and intracellular

messengers.
Fatty Acid Degradation and Synthesis Mirror
Each Other in Their Chemical Reactions
 β-OXIDATION

Utilization of FA as Fuel Requires 3 Stages

Processing

1. Lipids must be mobilized : TAG are degraded to FA &

glycerol, released & transported to the energy- requiring
tissues.

2. At these tissues, FA must be activated and transported

into mitochondria for degradation (oxidation)

3. FA are broken down in a step-by-step fashion into acetyl

coA, which is then processed in the citric acid cycle.
3. Carnitine Carries Long-Chain Activated FA
into Mitochondrial Matrix

CDSP - Carnitine Deficiency Systemic Primary

Acetyl CoA, NADH, and FADH2 Are Generated in Each Round of Fatty Acid Oxidation
The b-Oxidation of fatty acyl-CoA:
1. The first enzyme catalyses the
formation of a trans a, b double
bond, using FAD as cofactor. This
enzyme is linked to electron
transport chain via electron
transferring flavoprotein
2. Hydration of the double bond by
enoyl-CoA hydratase to form L-b-
hydroxyacyl-CoA.
3. NAD+-dependent
dehydrogenation by L-b-
hydroxyacyl-CoA dehydrogenase
to form b-ketoacyl-CoA.
4. Ca—Cb cleavage in athiolysis
reaction with CoA, catalysed by
thiolase, producing acetyl-Coa and
a new fatty acyl-CoA with two less
carbon units.
 Once in mitochondria, the fatty acyl
CoA is subjected to beta oxidation.

Utilization of FA for oxidation and

generation of ATP is achieved in the
following three steps;

1. beta-oxidation of fatty acid chain

yielding acaty-CoA.

2. Entry of actyl-CoA in citric acid

cycle yielding NADH, FADH2 and
GTP.

3. Utilization of NADH and FADH2 in

oxidative phosphorylation generating
ATP.
The first Fatty acyl-CoA
dehydrogenase enzyme of b-oxidation
pathway is linked to ETC and it
directly transfers the electrons to
Coenzyme Q in ETC via FADH2.
 The four steps of b-oxidation
are repeated to get FA
completely converted to acetyl-
CoA.
For example for a 16 carbon
fatty acid, Palmityl-CoA, it will
take 7 cycle of b-oxidation to
generate 8 acetyl-CoA.
Thus there will be production of
7 FADH2, 7 NADH molecules
during the b-oxidation cycles.

From 8 acetyl-CoA there will be

generation of;
8 GTPs, 8 FADH2, 24 NADH
and 16 CO2
Complete Oxidation of Palmitate Yields 106
or 129 Molecules of ATP

Net ATP yield:

( 8 x 10 ) + (7 x 1.5 ) + ( 7 x 2.5 ) – 2 = 106
or
(8 x 12) + (7 x 2 ) + (7 x 3 ) – 2 = 129
Oxidation of unsaturated fatty acids
All the steps are same except, and
additional enzyme called enoyl-CoA
isomerase is required to convert the
cis-double bond to trans double bond
that can be recognized by enoyl-CoA
hydratase.
Now the rest of the chain can be
oxidized as described before.
When more than one bonds
are unsaturated, then one
more additional enzyme is
used to saturate the second
double bond using NADPH.

This enzyme is called 2,4

dienoyl reductase.
This is followed by
isomerization reaction and b-
oxidation.
What about odd-chain fatty acids;
 Peroxisomal oxidation of
fatty acids:
Most of the steps are same
as b-oxidation in
mitochondria except that
the first dehydrogenase is
not linked to ETC in
peroxisomes.
Electrons from the first
reaction are transferred
directly to O2 producing
hydrogen peroxide.
Peroxisomal enzymes are
up-regulated when fat rich
diets are consumed.
Generally very long chain
FA diffuse into peroxi-
somes, get acivated by long
chain fatty acyl-CoA
synthase and then they are
oxidized toshort chain FA.
α-Oxidation ( Peroxisomal)
 Omega-oxidation:
This is a rare pathway of fatty
acid oxidation where FA
oxidation starts from the farther
most carbon (w-carbon).
Enzymes for this pathway are
located in endoplasmic
reticulum of vertibrates.
Ω-Oxidation: Endoplasma reticulum of liver & kidney
medium chain FA
ω-Oxidation
 Ketone Bodies: Acetyl-CoA
produced in liver as a result of b
oxidation, can go to CAC or it can
be converted to ketone bodies and
exported to other tissues for energy
generation.
Ketone bodies are produced when
glucose is not available as fuel
source,
 In cases of extreme starvation of
untreated diabetes (in both cases
glucose availability to tissues are
very low), liver starts
gluconeogenesis (synthesis of
glucose). This process uses CAC
intermediates such as oxaloacetate,
and thus the consumption of Acetyl-
CoA in CAC is slowed down.
These leads to excess of acetyl-CoA
in liver.
In order to meet the energy demand
by other tissues, liver catabolizes
fatty acids, produces excess of
acetyl-CoA and then produces
ketone bodies which are tranported
by blood to muscle and brain.
Ketone body formation regenerates
free CoA which are required for b-
oxidation.
 In untreated diabetes, the concentration of ketone bodies (two of which are
acids) in blood increases so much that it decreases the pH of blood. This
condition is called “acidosis” which can lead to coma or death.

High concentration of ketone bodies in blood and urine is referred as “ketosis”.

Due to high concentration of acetoacetate, which is converted to acetone, the
breath and urine of the untreated diabetic patients smells like acetone.
Ketone Bodies Are a Major Fuel in Some Tissues
FATTY ACID SYNTHESIS
LOCATION : Liver and adipose cytoplasm
Fatty acid synthase multienzyme complex
• FA synthesis starts with the carboxylation of acetyl CoA
to malonyl CoA. This irreversible reaction is the
committed step in fatty acid synthesis.
• Mammals lack the enzymes to introduce double bonds at carbon
atoms beyond C-9 in the fatty acid chain.
• Hence mammals cannot synthesize linoleate (18:2 cis-9, 12) and
linolenate (18:3 cis-9, 1 2 ,15) .
• Linoleate and linolenate are the two essential fatty acids.
• The term essential means that they must be supplied in the diet
because they are required by an organism and cannot be
synthesized by the organism itself.
• Linoleate and linolenate furnished by the diet are the starting
points for the synthesis of a variety of other unsaturated FA
Synthesis of Triglycerides
Hormonal control of Fatty acid synthesis and catabolism
Arachidonate is the major precursor of eicosanoids.
Prostaglandin synthase catalyzes the first step in a pathway leading to PG, PC, TX
Lipoxygenase catalyzes the init ial step in a pathway leading to leukotrienes (LT)
• Prostaglandins stimulate inflammation, regulate blood flow to
particular organs, control ion transport across membranes,
modulate synaptic transmission, and induce sleep.
 Sphingolipids
The core of sphingolipids is the long-chain amino alcohol,
sphingosine. Amino acylation, with a long chain fatty acid,
at carbon 2 of sphingosine yields a ceramide.

Sphingosine Ceramide

• Sphingomyelin, synthesized by the transfer of phosphorylcholine

from phosphatidylcholine to a ceramide in a reaction catalyzed by
sphingomyelin synthase.

• Glycosphingolipids: cerebrosides, sulfatides, globosides and

gangliosides.
Disorders Associated with Abnormal Sphingolipid Metabolism
Sphingolipidosis
R represents the linkage to protein in the secreted forms, sphingolipid (ceramide) in the
cell-surface bound form, open square = GlcNAc, open diamond = galactose, filled
square = fucose, filled diamond = GalNAc. The linkage in the glycolipid form may
include a glucose in a β-1,3 or β-1,4 to the initial galactose residue.
Defective Glycoprotein Degradation (LSD)
The process of cholesterol synthesis has five major
steps:

1. Acetyl-CoAs are converted to 3-hydroxy-3-

methylglutaryl-CoA (HMG-CoA)

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based

molecule, isopentenyl pyrophosphate (IPP), with the
concomitant loss of CO2

4. IPP is converted to squalene

5. Squalene is converted to cholesterol.

The cellular supply of cholesterol is maintained
at a steady level by three distinct mechanisms:

1. Regulation of HMGR activity and levels

2. Regulation of excess intracellular free cholesterol

through the activity of acyl-CoA:cholesterol
acyltransferase, ACAT

3. Regulation of plasma cholesterol levels via LDL

receptor-mediated uptake and HDL-mediated reverse
transport.
Apoprotein Classifications
Composition of the Major Lipoprotein Complexes
Hyperlipoproteinemia
Hypolipoproteinemia
Disorders of Lipoprotein Metabolism
Bile Acids as Metabolic Regulators
Bile acids were originally identified as being involved in
four primary physiologically significant functions:
1. their synthesis and subsequent excretion in the feces
represent the only significant mechanism for the
elimination of excess cholesterol.

2. bile acids and phospholipids solubilize cholesterol in the

bile, thereby preventing the precipitation of cholesterol in
the gallbladder.

3. they facilitate the digestion of dietary triacylglycerols by

acting as emulsifying agents that render fats accessible to
pancreatic lipases.

4. they facilitate the intestinal absorption of fat-soluble

vitamins.
Summary