METABOLISME LEMAK

Ika Nurzijah
Department of Pharmacology and Clinical Pharmacy
Apakah yang dimaksud
dengan senyawa lemak ?

SENYAWA LEMAK
Merupakan suatu senyawa
hidrofobik yang memiliki rantai
karbon panjang yang
berhubungan satu sama lain,
lemak tidak larut air.
FUNGSI SENYAWA LEMAK :
q  Penyusun membran sel dan mengatur
transport senyawa antara lingkungan
ekstraseluler dan intra seluler
(Fosfolipid)
q  Sumber energi jaringan (asam lemak
dan trigliserid)
q  Substrat untuk pembentukkan hormon
gonad dan adrenal
q  Sebagai surfaktan di paru-paru,
menjaga fungsi alveoli
q  Penyusun mielin, menjaga ketelitian
transmisi syaraf
q  Merupakan signaling molecules dan
penting dalam pembentukkan enzim
serta merupakan ligand reseptor intrasel
(diasilgliserol)
 SENYAWA
LEMAK
SEDERHANA
DAN
KOMPLEKS
 ASAM LEMAK

FACTS !

Asam lemak jenuh :

§  Rantai karbon jenuh (tidak memiliki
ikatan rangkap)
§  Titik lebur tinggi
§  Ikatan van der walls tinggi, berbentuk
padatan pada suhu ruang

Asam lemak tak jenuh :

§  Rantai karbon memiliki ikatan rangkap
§  Titik lebur rendah
PROSES BIOKIMIAWI
ASAM LEMAK

▪  BIOSINTESIS ASAM LEMAK DARI

SITRAT
▪  BETA-OKSIDASI ASAM LEMAK MENJADI
ASETIL CO-A
▪  K E T O G E N E S I S P A D A K O N D I S I
KEKURANGAN INSULIN
LIPOGENESIS DAN LIPID KATABOLISME

Acyl-CoA synthase

Plasma membrane Acyl-CoA dehydrogenase

Palmitoyltransferase 1 Tricarboxylic acid

Palmitoyltransferase 1
(CPT 1)

Elongation of very long

chain fatty acid protein 6

Stearoyl-CoA desaturase 1
Liver cells
1

4
KETOGENESIS
 Gangguan Klinis terkait dengan proses biokimiawi asam lemak

Diabetes Ketoasidosis

Beta oksidasi asam lemak

pada kondisi defisiensi
insulin à produksi ketone
bodies (acetone, β-
hydroxybutyrate, dan
acetoacetate) à
metabolic acidosis,
dehidrasi, kekurangan
cairan dan elektrolit
Eicosanoids are from 20-carbon poylunsaturated fatty acid

1.  Eicosanoids are a family of very

potent biological signaling molecule
2.  In response hormonal or other
stimuli, phospholipase A2 induces the
release of arachidonic acid from
membrane
3.  Arachidonic acid converts into PGH2
by cyclooxygenase (COX)
4.  COX-1 regulates the secretion of
gastric mucin
5.  COX-2 mediates inflammation, pain
and fever
6.  Thus, pain can be relieved by
inhibiting COX-2
Aspirin is irreversible inhibitor
NSAID, nonsteroidal antiinflammatory
drug

Thromboxane induce constriction of

blood vessels and platelet aggregation

Low doses of aspirin reduce the

probability of hear attacks and strokes by
reducing thromboxane production
COX-2 specific cyclooxygenase inhibitors used as pain relievers
LEUKOTRIENES VS ASTHMA
 The linear pathway from arachidonate to leukotrienes

5-LOX inhibitors include drugs, such as meclofenamate sodium

and zileuton.
Some chemicals found in trace amounts in food, as well as some dietary
supplements, have been shown to inhibit 5-LOX; these include baicalein,
caffeic acid, curcumin, hyperforin and St John's wort
TRIGLISERIDA

u  TRIGLISERIDA : merupakan ester

dari asam lemak dan alkohol
trifungsional (gliserol).
u  Memiliki nama lain triasilgliserol
(TAG atau triasilgliserida)
u  Penyusun utama jaringan adiposa
u  Jenis trigliserida yang ditemukan di
sirkulasi sistemik menggambarkan
komposisi asam lemak trigliserida
yang tersedia di jaringan adiposa
METABOLISME TRIGLISERIDA

Key concepts: absorption

q Triglyceride (i.e. energy) assimilation is key to the
survival of the organism.
q Dietary triglyceride must be hydrolyzed to fatty acids,
mono-glycerides and glycerol prior to absorption.
q Fatty acids must partition to micellar phase for
absorption.
q For transport, triglyceride must be reconstituted from
glycerol and fatty acid and incorporated into
chylomicrons.
METABOLISME TRIGLISERIDA

glycogenesis

lipogenesis

lipolisis

Katekolamin (adrenalin) à
meningkatkan lipolisis dan pelepasan
asam lemak dari jaringan adiposa à
GPCR (adenosine monophosphate,
protein kinase A aktivitasnya naik)
-  An additional factor in the balance between biosynthesis and degradation of fa is
that approximately 75% of all fatty acids released by lipolysis are reesterified to
form triacylglycerol rather than used for fuel by triacylglycerol cycle

-  The level of free fatty acids in blood reflects both the rate of released fa and the
balance between the synthesis and breakdown of TAG in adipose tissue and liver
Adipose tissue generates G3P by glyceroneogenesis

Glyceroneogenesis has multiple roles In

adipose tissue, it controls the rate of FA
released to blood
BIOSINTESIS TRIGLISERIDA DAN FOSFOLIPID

Glycerol-3-phosphate acyltransferase (GPATs)

Acylglycerol-phosphate acyltransferase (AGPATs)

Acyl-CoA-Diacylglycerol
Acyltransferase (DGATs)
Cytidine diphosphate
diacylglycerol
Kennedy Pathway

Metilasi
-  Flux through the triacylglycerol cycle between liver and adipose tissue is controlled
by PEPCK activity

-  Glucocorticoid hormone regulate the level of PEPCK reciprocally in the liver and
adipose tissue
Glucocorticoid hormones stimulate glyceroneogenesis and
gluconeogenesis in the liver suppress glyceroneogenesis in the adipose
tissue by reciprocal regulation of the gene expressing PEPCK in the two
tissues
 Gangguan Klinis terkait dengan metabolisme trigliserida

Peningkatan lipolisis pada jaringan

adiposa (penderita obesitas) akan
meningkatkan jumlah FFA yang
dilepaskan ke pembuluh darah à
gangguan fungsi beta sel pankreas,
liver, otot tulang, dan hati

Pasien sehat keturunan DM tipe 2,

kehilangan kemampuan insulin
dalam menghambat lipolisis
trigliserida à predisposisi DM

PANKREATITIS
-  High levels of free fatty acids in blood interfere with glucose utilization in
muscle and promote the insulin resistance that leads to type2 diabetes

-  Thiazolidinediones reduce the levels of fatty acid in the blood and increase
sensitivity to insulin
Thiazolidinediones activate a nuclear receptor, peroxisome proliferator-activated
receptor γ (PPARγ), which induces the activity of PEPCK (Phosphoenolpyruvate
carboxykinase)

They increase the rate of glyceroneogenesis, thus increasing the resynthesis of

triacylglycerol in adipose tissue and reducing the amount of free fatty acid in the blood
 Regulation of triacylglycerol synthesis by insulin

Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus
lack insulin. In uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising
from catabolism of carbohydrates and proteins is shunted instead to ketone body production

People in severe ketosis smell acetone, so the condition is mistaken for drunkenness
SINTESIS DAN METABOLISME
KOLESTEROL
 HMG CoA Reductase
(More Than Cholesterol Synthesis)
Acetyl CoA

HMG CoA
HMG CoA Reductase
Isopentenyl
Mevalonate
adenine
(transfer RNA)
Prenylation of Farnesyl Pyrophosphate
signalling peptides
(ras, rho, etc.)
Ubiquinones
Dolichols (CoQ-10, etc.)
Cholesterol
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.
 NORMAL CHOLESTEROL METABOLISM

0.8 G Tissue
SYN CHOL*
pools
70G

0.4 G CHOL

*SYN CHOL = CHOLESTEROL SYNTHESIS

 NORMAL CHOLESTEROL METABOLISM

0.85 G 0.8 G Tissue

ABS CHOL SYN CHOL*
pools
70G

1.3 G
CHOL

.20 G CHOL 0.65 G CHOL

50%

.20 G
0.4 G CHOL .65 G

*SYN CHOL = CHOLESTEROL SYNTHESIS

 NORMAL CHOLESTEROL METABOLISM

▪  Key concepts: synthesis

▫  Primary synthetic sites are extrahepatic, but liver is
key regulator of homeostasis
▪  Key concepts: absorption
▫  Largest source is biliary secretion, not diet.
▫  Normal absorption: 50%
▫  For cholesterol to be absorbed it must:
■  undergo hydrolysis (de-esterification by
esterases)
■  be incorporated into micelles
■  be taken up by cholesterol transporter
■  be re-esterified and incorporated into
chylomicrons
NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day

400 mg/day

Oil phase
NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day

400 mg/day

17,400 mg/day
Oil phase

Plant sterols compete

For cholesterol here
NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day

400 mg/day

17,400 mg/day
Oil phase

850 mg/day
Ezetimibe competes
For cholesterol here
NORMAL CHOLESTEROL ABSORPTION
1,300 mg/day

400 mg/day

17,400 mg/day
Oil phase

850 mg/day

Defect in ABCG5/G8
transporter causes
phytosterolemia
Gallstones

Gallstones are hardened

deposits of bile that can
form in your gallbladder.
Bile is a digestive fluid
produced in your liver and
stored in your gallbladder.
When you eat, your
gallbladder contracts and
empties bile into your small
intestine (duodenum).
 NORMAL CHOLESTEROL METABOLISM

▪  Role of Bile Salts, cholesterol, phospholipids

in gall stone formation.
▪  Importance of Bile Salts for cholesterol
absorption
§  Bile salt absorption inhibitors
–  Bile acid binding compounds:
•  Welchol
•  Cholestyramine
•  Colestipol
•  Fiber

–  Surgery: Partial ileal bypass.