METABOLISME LIPID

F. Ferdinal

BAGIAN BIOKIMIA dan BIOLOGI MOLEKULER

FAKULTAS KEDOKTERAN
UNIVERSITAS TARUMANAGARA

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 oligosakarida3. 3.
Other complex lipids:Sulfolipid,aminolipid, Lipoprotein
III. Precursor & Derived Lipids: Steroids, Lipid-soluble Vit,
Eicosanoids, KB.

1. Simple lipids: Esters of fatty acids with various alcohols.

a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state.
b. Waxes: Esters of fatty acids with higher molecular weight monohydric
alcohols.

2. Complex lipids: Esters of fatty acids containing groups in

addition to an alcohol and a fatty acid.

a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a

phosphoric acid residue. They frequently have nitrogen containing bases and
other substituents, eg, in glycerophospholipids, the alcohol is glycerol and in
sphingophospholipids the alcohol is sphingosine.
b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid,
sphingosine,
and carbohydrate.
c. Other complex lipids: Lipids such as sulfolipids and aminolipids.
Lipoproteins may also be placed in this category.

3. Precursor and derived lipids: These include fatty acids, glycerol,

steroids, other alcohols, fatty aldehydes, ketone bodies (Chapter 22), hydrocarbons,
ipid-soluble vitamins, and hormones.

The LIPID MAPS (LIPID Metabolites And Pathways Strategy)

Structural relationships of the major classes of lipids.

Klasifikasi yang lain :

MAJOR Class LIPID
1. FA
2. TAG
3. Fosfolipid:
- Gliserofosfolipid: PC, PE, PI, PS
- Sfingolipid:sfingomielin, cerebroside, gangliosida
4. Kolesterol:

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; Hexadecacoic acid
Unsaturated : berakhiran enoic, ex: Eicosatetraenoic acid
Numbering
Mulai dari atom C karboksil sebagai nomor 1, selanjutnya
2, 3, 4 etc atau , , , , etc, tetapi atom C terminal
disebut sebagai atom C (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 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 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

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

Common Saturated Fatty Acids

Unsaturated Fatty Acids

Examples of oils
Olive oil from Oleo europa (olive tree)
Corn oil from Zea mays
Peanut oil from Arachis hypogaea
Cottonseed oil from Gossypium
Sesame oil from Sesamum indicum
Linseed oil from Linum usitatissimum
Sunflower seed oil from Helianthus
annuus
Rapeseed oil from Brassica rapa
Coconut oil from Cocos nucifera

H3C

COOH
CH3

CH3

CH3

CH3

PHYTANIC ACID
A plant derived fatty acid with 16 C and branches at C 3,
C7, C11 and C15. (metab in RE )
Present in dairy products and ruminant fats.
A peroxisome responsible for the metabolism of phytanic
acid is defective in some individuals.
(phytanol-CoA dioxygenase) -oxidation
This leads to a disease called Refsums disease
Refsums disease is characterized by peripheral
polyneuropathy, cerebellar ataxia and retinitis pigmentosa

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 dab fungsi membran sel

Transport kolesterol
Pembentukan liporotein
Mencegah Fatty Liver

Cis - Trans Fatty Acids

Lipid storage diseases

also known as sphingolipidoses
genetically acquired
due to the deficiency or absence of a catabolic
enzyme
examples:
Tay Sachs disease
Gauchers disease
Niemann-Pick disease
Fabrys disease
http://www.ninds.nih.gov/disorders/lipid_storage_
diseases/lipid_storage_diseases.htm

Fatty Acid Metabolism

Degradation and Synthesis

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

TAG Are Highly Concentrated Energy Stores

TAG are highly concentrated stores of metabolic energy.

38 kJ (9 kcal g-l), vs 17 kJ (4 kcal g-I) for KH and proteins

Basis of difference: FA are much more reduced

and
nonpolar stored in anhydrous form.
( 6.75 X vs polar glycogen )

BW 70 kg: reserve energy: 100.000; 24.000; 600; 40 kcal

for TAG, Protein, Glycogen and Glucose, respectively.

Glycogen & Glucose stored: 24 Hs; TAG : several weeks

Golden Plover: Alaska to southern tip of south America

2400 miles over open ocean.

Dietary Lipids Are Digested by Pancreatic Lipases

TAG incorporated into micelles, composed of bile

salts
Steatorrhea, bile salts (<<) due to liver disease

Dietary Lipids Are Transported in Chylomicrons

CM : 200 nm, TAG, C, CE, PL, fat-soluble vitamin

Apo-B48

dan

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.

1. TAG are hydrolyzed by HS Lipases

Mobilization of triacylglycerols

Glycerol formed by lipolysis is absorbed

by the liver

2. FA are linked to CoA-SH before they are oxidized

E. Kennedy & A Lehninger (1949): oxidized in mitochondria

Paul Berg

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

Complete Oxidation of Palmitate Yields 106

Molecules of ATP

Net ATP yield:

( 8 x 10 ) + (7 x 1.5 ) + ( 7 x 2.5 ) 2 = 106

 An Isomerase and a Reductase Are Required for the Oxidation of

Unsaturated Fatty Acids
two additional enzymes an isomerase and a reductase are needed to degrade a wide
range of unsaturated fatty acids.
oxidation of polyunsaturated fatty acids

Odd-Chain Fatty Acids Yield Propionyl CoA in

the Final Thiolysis Step

Ketone Bodies Are Formed from AcetylCoA

When Fat Breakdown Predominates

Ketone Bodies Are a Major Fuel in Some Tissues

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

Composition of the Major Lipoprotein Complexes

Hyperlipoproteinemia

Hypolipoproteinemia

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)

Apoprotein Classifications

 Prostaglandins stimulate inflammation, regulate blood flow to

particular organs, control ion transport across membranes,
modulate synaptic transmission, and induce sleep.

-Oxidation
Medium chain (C 10 -12), Ret.endoplama dan ginjal
(Rescue Pathway)

Synthesis of Triglycerides

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

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 -1,3 or -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-3methylglutaryl-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.

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.