PHARMACOLOGY OF CHOLESTEROL

AND LIPOPROTEIN METABOLISM

dr. Mara Imam Taufiq Siregar, S.Pdi, M.Biomed

FACULTY OF MEDICINE
JAMBI UNIVERCITY
2016
 Learning objective

1. Understand the chemical composition and differences

between fats
2. Explain the structural and functional processes of
triglycerides, phospholipids, and sterols
3. Describe the process of fat digestion and absorption
4. Discuss the different types of lipoproteins in the body
5. What is arteriosclerosis? - Link between
arteriosclerosis and cholesterol
6. Hyperlipidemias
7.Anti-hyperlipidemic Agents - Classes
Fatty Acids

 The Length of the Carbon Chain

◦ long-chain, medium-chain, short-chain
 The Degree of Unsaturation
◦ saturated, unsaturated (monounsaturated,
polyunsaturated)
 The Location of Double Bonds
◦ omega-3 fatty acid, omega-6 fatty acid
The Length of the Carbon
Chain

Short-chain Fatty Acid

(less than 6 carbons)
Medium-chain Fatty Acid
(6-10 carbons)

Long-chain Fatty Acid

(12 or more carbons)
Fatty Acids are Key Building Blocks

 Saturated Fatty Acid

 All single bonds between carbons
Monounsaturated Fatty Acid
(MUFA)

One carbon-carbon double bond

Polyunsaturated Fatty Acid
(PUFA)

More than one carbon-carbon double bond

 Location of Double Bonds
 PUFA are identified by position of the
double bond nearest the methyl end (CH3)
of the carbon chain; this is described as a
omega number;
 If PUFA has first double bond 3 carbons
away from the methyl end=omega 3 FA
 6 carbons from methyl end=omega 6 FA

Omega-3 Omega-6
 Degree of Unsaturation
 Firmness
◦ saturated vs. unsaturated
 Stability
◦ oxidation, antioxidants
 Hydrogenation
◦ advantages, disadvantages
 Trans-Fatty Acids
◦ from hydrogenation
Cis-fatty acid:H’s on same side of the double bond; fold into
a U-like formation; naturally occurring;
Trans-fatty acid: H’s on opposite side of double bond; more
linear; occur in partially hydrogenated foods;
 Triglycerides

 Structure
◦ Glycerol + 3 fatty acids
 Functions
◦ Energy source
 9 kcals per gram
 Form of stored energy in
adipose tissue
◦ Insulation and protection
◦ Carrier of fat-soluble vitamins
◦ Sensory properties in food
 Triglycerides
 Food sources
◦ fats and oils
 butter, margarine, meat, snack
foods, salad dressings, dairy
products, nuts, seeds
◦ Sources of omega-3 fatty acids
 Soybean, walnut, flaxseed oils
 Salmon, tuna, mackerel
◦ Sources of omega-6 fatty acids
 Vegetable oils
 Phospholipids

 Structure
◦ Glycerol + 2 fatty acids + phosphate
group
 Functions
◦ Component of cell membranes
◦ Lipid transport as part of lipoproteins
◦ Emulsifiers
◦ Phosphatidylcholine
 Food sources
◦ Egg yolks, liver, soybeans, peanuts
 Sterols: Cholesterol

 Functions
◦ Component of cell membranes
◦ Precursor to other substances
 Sterol hormones
 Vitamin D
 Bile acids
 Synthesis
◦ Made mainly in the liver
 Food sources
◦ Found only in animal foods
Fatty Acids in Common Food Fats
 What Are the Lipid Related Risk
Factors for CVD?

• High LDL Cholesterol and Low HDL

Cholesterol
• A diet high in cholesterol
• A diet high in saturated fat
• A diet high in trans-fatty acids
 Lipid Digestion

 In the Mouth
◦ hard fats begin to melt; lingual lipase
 In the Stomach
◦ gastric lipase--SCFA
 In the Small Intestine
◦ release of CCK; bile-emulsifier; fat drawn into
surrounding watery fluids; intestinal lipases;
remove each TG fatty acid; leave glycerol;
 Bile Routes
◦ reabsorbed or trapped by dietary fiber
 Digestion occurs by Hydrolysis of
Macromolecules
Emulsification: physical
dispersion of lipids into
smaller droplets
carbohydrate protein
Hydrolysis: +
pancreatic amylase chemical bile salts fat globules
separation of trypsin
subunits emulsification
peptides droplets
maltase hydrolysis
cell of peptidase lipase Hydrolysis
intestinal glucose
villus
amino acids

pH = basic pH = basic pH = basic

lymphatic
blood capillary blood capillary
capillary

Carbohydrate digestion Protein digestion Fat digestion

Summary of Fat Absorption
 Overview cholesterol metabolism

Deliver dietary TG to
muscle
and adipose tissue

Transport endogenous TG and cholesterol

 Cholesterol Transport by Blood
Lipoproteins

 Cholesterol, cholesterol esters, triacylglycerols, &

phospholipids are insoluble and must travel via
lipoproteins
Anatomy of a Lipoprotein
 Apolipoproteins

•Structural
determinants of
lipoproteins
•Enzyme cofactors
•Ligands for binding
to lipoprotein
receptors
Table 25–1. Composition of the Lipoproteins in Plasma of Humans.
Lipoprotein Source Diameter Density Protein Lipid Main Lipid Apolipoproteins
(nm) (g/mL) (%) (%) Components
1
Chylomicrons Intestine 90–1000 < 0.95 1–2 98–99 Triacylglycerol A-I, A-II, A-IV,
B-48, C-I, C-II,
C-III, E
Chylomicron Chylomicrons 45–150 < 1.006 6–8 92–94 Triacylglycerol, B-48, E
remnants phospholipids,
cholesterol

VLDL Liver (intestine) 30–90 0.95–1.006 7–10 90–93 Triacylglycerol B-100, C-I, C-II,
C-III
IDL VLDL 25–35 1.006–1.019 11 89 Triacylglycerol, B-100, E
cholesterol
LDL VLDL 20–25 1.019–1.063 21 79 Cholesterol B-100

HDL Liver, intestine, VLDL, Phospholipids, A-I, A-II, A-IV,

chylomicrons cholesterol C-I, C-II, C-III,
2
HDL1 20–25 1.019–1.063 32 68 D, E

HDL2 10–20 1.063–1.125 33 67

HDL3 5–10 1.125–1.210 57 43
3
Preβ-HDL <5 > 1.210 A-I

Albumin / free fatty Adipose tissue > 1.281 99 1 Free fatty acids
acids
Abbreviations: HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low density
lipoproteins.
1Secreted with chylomicrons but transfers to HDL.
2Associated with HDL2 and HDL3 subfractions.
3Part of a minor fraction known as very high density lipoproteins (VHDL).
The formation and secretion of (A) chylomicrons by an intestinal cell and (B)
very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic
reticulum; SER, smooth endoplasmic reticulum; G, Golgi apparatus; N, nucleus; C,
chylomicrons; VLDL, very low density lipoproteins; E, endothelium; SD, space of Disse,
containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into
lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of
carbohydrate residues in G, they are released from the cell by reverse pinocytosis.
Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse
and then into the hepatic sinusoids through fenestrae in the endothelial lining.
Triglyceride-Degrading Enzymes

• LPL (Lipoprotein Lipase)

LPL is extracellular on the walls of blood capillaries,
anchored to the endothelium. Triacylglycerol (TG) is
hydrolyzed to free fatty acids plus glycerol. Some of
the released free fatty acids return to the circulation
(bound to albumin) but the bulk is transported into the
tissue (mainly adipose, heart, and muscle (80%), while
about 20% goes indirectly to the liver.
Triglyceride-Degrading Enzymes

• HL (Hepatic Lipase)

HL is bound to the sinusoidal surface of liver cells,

where it also hydrolyzes TG to free fatty acids plus
glycerol. This enzyme, unlike LPL, does not react
readily with chylomicrons or VLDL but is concerned
with TG hydrolysis in chylomicron remnants and HDL
metabolism.
Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; ,
apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C,
cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-
related protein.) Only the predominant lipids are shown.
Metabolic fate of very low density lipoproteins (VLDL) and production of
low-density lipoproteins (LDL). (A, apolipoprotein A; B-100, apolipoprotein B-
100; © apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG,
triacylglycerol; IDL, intermediate-density lipoprotein; C, cholesterol and cholesteryl
ester; P, phospholipid.) Only the predominant lipids are shown. It is possible that
some IDL is also metabolized via the LRP.
Enzymes and Transfer Proteins

• LCAT (Lecithin:Cholesterol Acyltransferase)

• Formation of cholesterol esters in lipoproteins

• ACAT (Acyl-CoA:Cholesterol Acyltransferase)

• Formation of cholesterol esters in cells

• CETP (Cholesterol Ester Transfer Protein)

Transport of cholesterol between the
tissues in humans. (C, unesterified cholesterol;
CE, cholesteryl ester; TG, triacylglycerol; VLDL,
very low density lipoprotein; IDL, intermediate-
density lipoprotein; LDL, low-density lipoprotein;
HDL, high-density lipoprotein; ACAT, acyl-
CoA:cholesterol acyltransferase; LCAT,
lecithin:cholesterol acyltransferase; A-I,
apolipoprotein A-I; CETP, cholesteryl ester
transfer protein; LPL, lipoprotein lipase; HL,
hepatic lipase; LRP, LDL receptor-related protein.)
Atherosclerosis
Definition
 Atherosclerosis: A disease of large and
medium-sized arteries that results in
progressive accumulation of smooth
muscle cells and lipids within the
intima.
 Typically kills by inducing myocardial
infarction

 Different from arteriosclerosis

(hardening of the arteries), which is
due to calcification of the arterial wall.
Pathogenesis

 Fatty streak
 Intimal
thickening
 Plaque
 Thrombosis or
aneurysm
Oxidized LDL Induces leukocyte “homing”

Vessel Lumen
Monocyte
Adhesion LDL
Molecules

Endothelium
LDL

Cytokines
Oxidized LDL

Macrophage
Intima
Macrophages take up modified LDL

Monocyte Vessel Lumen

Adhesion LDL
Molecules

Necrosis frees Endothelium

the modified LDL
LDL

Oxidized LDL
Taken up by
Macrophage

Intima
Foam Cell Macrophage
Foam cells and macrophages
Etiology
 What is the "trigger" for initiation of the
disease?
◦ Hemodynamic stress
◦ Bacterial infection, particularly periodontal
disease
◦ High lipid cocentrations
Etiology

 Fatty streaks are typically found in

teenagers, so the disease begins early.
 Occurrence increases with
◦ obesity
◦ diabetes
◦ high lipid/cholesterol diets
◦ increasing age
◦ high blood pressure
 Genetic factors are prevalent (like in
familial hypercholesterolemia)
Familial Hypercholesterolemia

 Incidence: 1 in 500
 The most common known form of genetic
disease
 Results in
◦ 2X to 6X increase in serum cholesterol
◦ Severe and early atherosclerosis and myocardial
infarction
◦ Diagnosed on the above two items, and a family
history
 Etiology
◦ Mutations in the gene coding for LDL receptors
Pharmacological Strategy for Controlling Hyperlipidemia

Diet Biosynthesis
2.STATINS
1.EZETIMIBE
HMG CoA reductase

LDL-R
Serum Cholesterol Cellular Cholesterol

Conversion to
Bile Acids hormones within
cells or storage
Re-absorption as granules
Intestine
Lipoprotein
3. BILE ACID catabolism 4. FIBRATES
SEQUESTRANTS
Feces
 OH
OH

N
F O

1. EZITIMIBE
Inhibitor of cholesterol absorption
Cholesterol Absorption in the Intestine

1000 mg

Inhibitors

Resins

Plant stanols NPC1L1

(Ezetimibe)
 Niemann-Pick C1 Like 1

OUT

IN

SS
D
 NPC1L1, identified in 2000, was a gene of unknown function
related to Niemann-Pick C1 protein
 DNA sequence analysis predicted features of a hypothetical
cholesterol transporter
◦ Membrane protein expressed on cell surface
◦ Homologous to Niemann-Pick C1 (a protein known to be
involved in cholesterol movement)
◦ Expression regulated by cholesterol
◦ Sterol sensing domain
 Protein expression is restricted to the enterocytes of the proximal
small intestine
 Ezetimibe: Localization at Site
of Cholesterol Absorption
Absorption of cholesterol Ezetimibe localization
in intestine (hamster) at intestinal brush border (rat)

 Localizes at brush border of small intestine and prevents

uptake of cholesterol into enterocytes
 Decreases delivery of intestinal cholesterol to liver
resulting in
– Up-regulation of LDL-C–receptor synthesis
– Increased cholesterol clearance from the blood
Adapted from van Heek M et al Br J Pharmacol 2000;129:1748–1754; Brown WV Am J Cardiol
2001;87(suppl):23B–27B;
Sparrow CP et al J Lipid Res 1999;10:1747–1757.
 Metabolism of Ezetimibe

Ezetimibe O
OH H • Rapidly metabolized to an
active glucuronide
metabolite
N
F O • Both parent drug and
metabolite inhibit
Glucuronidation
F cholesterol absorption
OGlu
OH • Glucuronide metabolite
c
more potent than parent
drug in inhibiting
N cholesterol absorption
F O
Glucuronide • Repeated enterohepatic
F circulation results in long
duration of action
 Ezetimibe: Summary of
Pharmacokinetic Parameters
 Absorption
◦ Rapidly absorbed after oral administration
◦ Peak plasma concentration of active metabolite
in 1–2 hours
 Elimination
◦ Eliminated principally in feces after extensive
enterohepatic recirculation
◦ Elimination half-life of ~22 hours allows once-daily
dosing
 No induction of CYP 450 enzyme system
 No significant pharmacokinetic interactions with
commonly
used drugs
 Bioavailability unaffected by food
 Pharmacokinetics unaffected by age or gender

Adapted from Patrick JE et al Drug Metab Disp 2002;30:430–437; Summary of Product

Characteristics, EZETROL™, MSP.
 Ezetimibe = senyawa basa azetidione 
menurunkan lipid dan kolesterol
diabsorpsi diusus  dengan memblok
dinding ususnyaEzetimibe mengalami
glukoronidasi di usus dan senyawa aktif
glukoronidnyadiekskresikan ke empedu
oleh hati.
 Monoterapi : mengurangi kolesterol LDL
15 – 20 %
 Efek kombinasi statin dosis rendah + 10
mg ezetimbe ( menurunkan LDL sampai
50% )= simvastatin dosis 80 mg.
2. STATIN
STATIN
STATIN
 Semua preparat statin  antagonis
kompetitif HMG coA reduktase.
 Menginhibisi kerja HMG coA reduktase
 Golongan statin :
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
STATIN
 1950  penemuan cholestenum  tidak
digunakan lagi (akumulasi dihidrokolesterol
 bersifat sama dengan kolesterol.)
 Penicillium oitrium  memp. Efek
penghambat HMG coA reduktase.
 Penicillium brevecompactin  prefarat
compactin.
 Aspergillus terreus  prefarat mevinolin.
 Mevinolin : lovastatin
 Semisintetis mevinolin & compactin :
simvastatin, provastatin, atorvastatin.
 Sintestis de novo : fluvastatin, cerivastatin.
FARMAKOKINETIK STATIN
 Semua  per-oral.
 Prodrug: Lovastatin, simvastatin  mengandung cincin
lakton dihati  beta-hidroksiasid aktif.
 Mengalami first pass metabolism.
 Preparat aktif: pravastin, fluvastatin, atorvastatin,
cerivastatin.
 Absorbsi: melalui usus halus, bervariasi  atorvastatin
(12%), fluvastatin (>90%).
 Ekskresi: urin10 – 20%, sisanya feses.
 Ikatan protein plasma: provastatin (50%), fluvastatin,
atorvastatin (99%).
 Kadar puncak plasma: 1-4 jam, kembali ke kadar
baseline dalam 24 jam.
STATIN
3. BILE ACID SEQUESTRANTS
 Resin Pengikat Asam Empedu
Resin pengikat asam empedu

= polymer senyawa amin kuartener = resin penukar ion.

 Resin (positif) + asam empedu (negatif).

Ukuran resin besar  tidak akan diserap  resin + asam empedu  diekskresi
ke feses  asam empedu dalam saluran pencernaan terbuang (fisiologi normal,
95 % asam empedu akan diserap kembali) lemak dari makanan juga tidak
terserap oleh tubuh  merangsang sintesis asam empedu dengan peningkatan
jumlah reseptor LDL hingga uptake LDL oleh sel-sel hati(internalisasi) menjadi
lebih banyak  akibat kadar LDL di dalam plasma akan turun  Untuk
menyeimbangi peningkatan jumlah reseptor LDL, maka akan terjadi Upregulation
dari HMG-CoA reductase  Oleh karena itu penggunaan golongan Statin sebagai
inhibitor HMG-CoA reductase dapat meningkatkan efek resin.

Obat ini tidak memberikan efek pada pasien dengan hiperkolesterolemia familial
homozigot yang mempunyai reseptor yang tidak berfungsi, tetapi ia bermanfaat
pada pasien heterozigot dengan keadaan heterozigot yang dikombinasi dengan
reseptor tidak sempurna
Resin Pengikat Asam Empedu
 Efek terapi :
 1.LDL : ↓ 15-30 %
 2.HDL : ↑ 3-5 %
 3.TG : Tidak mengalami perubahan

 Kontra indikasi :
 1.Absolut : Disbetalipoproteinemia, TG >
400 mg/dl
 2.Relatif : TG > 200 mg/dl
Efek samping
 Gangguan GI :
1. Konstipasi  beri laksansia
2. Steatore karena meningkatnya buangan asam
lemak rantai panjang,

 Flaws cegah dengan banyak minum + makanan

berserat
 Hipokloremik metabolik asidosis
 Peningkatan ringan alkali fosfatase dan transaminase
 Pembentukan batu empedu tetapi tidak signifikan
 Hilangnya penyerapan vitamin A, D, Kepada dosis
tinggi (30 g/hari).
Kolestiramin

= anion ammonium kuartener penukar resin dengan inti stiren.

Gugus klorida kolestiramin dapat ditukar dengan anion lainnya, seperti

garam empedu dan lain-lain.

Mekanisme kerja :
Karena kolestiramin tidak diserap, maka setelah pemberian peroral, kolestiramin
akan mengikat garam empedu di dalam usus halus dan siap diekskresikan ke
dalam feces,sehingga ekskresi garam empedu meningkat 10 kali lipat (1-2 g/hari).
Ekskresi garam dan asam empedu menurunkan kadar asam empedu yang
kembali ke hepar, yang berfungsi menghambat enzim 7a-hidroksilase yang
mengkonversi kolesterol menjadi asam empedu,sehingga kolesterol banyak
dipecah oleh hepar.
Akibat meningkatnya katabolisme kolesterol di dalam hepatosit ini, enzim-
hidroksi-metilglutaril-CoA-reduktase (HMG CoAreduktase) yang mensintesa
kolesterol terangsang pula, tetapi pada keadaan normal sintesa kolesterol ini
lebih lambat dibanding pemecahannya, sehingga kolesterol dalam plasma dan
jaringan lain ditarik ke dalam hepar. Dengan demikian kolestiramin mampu
memobilisasi kolesterol dan menurunkan kadar LDL sebagai efek sekunder dari
aktifnya pula reseptor LDL hepatosit karena mobilisasi kolesterol oleh hepar akan
merangsang pembentukan reseptor LDL lebih banyak lagi oleh hepatosit itu
sendiri.
Cholestyramine(Questran®)
 Garam klorida dari resin penukar anion
dasar
cukup hidrofilik tetapi tidak larut dalam
air
 Bentuk bubuk
 Dosis : 4 gr/2x/hari/p.o & dititrasi naik
 Maks : 24 gr/hari
 Kontrol : lipid profile pada minggu ke-4
 Colesevelam(Welchol®)
 Tablet 625 mg, oval dan berselaput
 N-prop-2-enyldecan-1-amine; trimethyl-[6-
(prop-2-enylamino)hexyl]azanium; prop-2-en-
1-amine; 2(chloromethyl)oxirane; hydrogen
chloride; chloride
 Dosis : 6 tab x 625mg/4x/hari
 Maks : 4375 mg/hari
 Kontrol : LFT periodik dalam 1 tahun
 Colestipol(Colestid®)
 BM >
 Dasar pertukaran anion : kopolimer diethylenetriamine
+ 1-kloro-2, 3-epoxypropane± 1 dari 5 nitrogen
amina diprotonasi
 Sediaan :
 1.Tablet, kuning terang tidak berbau dan tidak berasa
2.Granules dan Flavored Granules
 Dosis : 5 gr/2x/hari
 Maks : 30 gr /hari

 Efikasi, mekanis mekerja, dan toksisitasnya sama

dengan kolestiramin. Hanya menurunkan kadar
kolesterol
4. FIBRATE
 FIBRATES
 Also called fibric acid derivatives
 Fibrates are mainly used for patients with
hypertriglyceridemias in which VLDL
predominate and in
dysbetalipoproteinemia
 this group of drugs is known to lower
plasma levels of fatty acid and
triacylglycerol
 Clofibrate was the first such drug,
developed in Japan in the 1960s
 FIBRATES
 The discovery of several other fibrate
drugs such as ciprofibrate, bezafibrate,
fenofibrate, and gemfibrozil has
revolutionized lipid-lowering research
 Prolonged use of some of these drugs like
clofibrate and ciprofibrate causes
peroxisome proliferation leading to
hepatomegaly and tumor formation in the
liver of rodents
 Only gemfibrozil and fenofibrate are
being used as lipid-lowering drugs in
humans.
 GEMFIBROZIL

 Gemfibrozil is absorbed quantitatively from the

intestine and is tightly bound to plasma proteins.

 It undergoes enterohepatic circulation and readily

passes the placenta.

 The plasma half-life is 1.5 hours. Seventy percent

is eliminated through the kidneys, mostly
unmodified.
 GEMFIBROZIL
The usual dose of gemfibrozil is 600 mg orally once or twice daily
Absorption of gemfibrozil is improved when the drug is taken with
food.
 Fenofibrate is a methylethyl ester that
is hydrolyzed completely in the
intestine. Its plasma half-life is 20
hours. Sixty percent is excreted in the
urine as the glucuronide, and about
25% in feces
 The empirical formula is C20H21O4Cl
 Brand name: Lofibra

FENOFIBRATES
FENOFIBRATES
MECHANISM OF ACTION
TERIMAKASIH