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7/18/2019 11. Sintesis Kolesterol
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Cholesterol Synthesis, transport, and
excretion
Abdul Salam M Sofro
Faculty of Medicine
YARSI University
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Learning objectives
• By the end of lectures, students are
expected to understand: –The process of cholesterol synthesis
and catabolism
–Cholesterol transport in bloodcirculation & excretion
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KasusIbu S usia 42 th mengeluh pada dokter
keluarganya bahwa sejak beberapabulan terakhir pemeriksaan profil
lipidnya kurang baik. Kolesterol total
dan trigliseridanya jauh di atas normal,
LDL di atas normal dan HDL cenderung
rendah. Pasien juga mengatakan sdh
tidak makan goreng-gorengan, serta
menghindari makan berlemak, tetapikadar senyawa-senyawa lipid tersebut
belum kembali normal.
Photo by: Lev Olkha
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Introduction
• Cholesterol present in tissue & in plasmalipoproteins either as free cholesterol or,combined with a long chain FA as
cholesteryl ester• It is synthesized in many tissues from
acetyl-CoA and is ultimately eliminatedfrom the body in the bile as cholesterol or
bile salts
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http://www.gugulipid.com/mechan.htm
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Lipid Structure
HO
Cholesterol
COOH
COOH
COOH
HO
HO
HO
+
Fatty Acids
Glycerol
COO
COO
COO
Triglycerides
COO
COO
OPOON
Phospholipid: Lecithin
+
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Acetyl-CoA is the source of all carbon atom in
cholesterol
• Five stages in biosynthesis of cholesterol: – Synthesis of Mevalonate, a six-carbon
compound, from acetyl-CoA
– Isoprenoid units are formed from mevalonate
by loss of CO2 – Six isoprenoid units condense to form the
intermediate squalene
– Squalene cyclisized to parent steroid,
lanosterol – Cholesterol is formed from lanosterol after
several further steps including the loss of threemethyl groups
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Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA ffrom
the mitochondrion to the cytosol. The rate limiting step occurs at the 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation
reactions are required to solubilize the isoprenoid intermediates in the pathway.
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Key concepts: synthesis
Primary synthetic sites areextrahepatic, but liver is key regulator
of homeostasis
Normal Cholesterol Metabolism
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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
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400 mg/day
1,300 mg/day
17,400 mg/day
Normal Cholesterol Absorption
Plant sterols competeFor cholesterol here
Oil phase
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Stage 5
• The conversion of lanosterol to
cholesterol
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Regulating Cholesterol Synthesis
Normal healthy adults synthesize cholesterol
at a rate of approximately 1g/day and
consume approximately 0.3g/day.
A relatively constant level of cholesterol in
the body (150 - 200 mg/dL) is maintained
primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is
regulated in part by the dietary intake of
cholesterol.
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• Regulation of HMG-CoA reductase:
– Reduced activity in fasting animals(reduced synthesis of cholesterol duringfasting)
– Feedback mechanism whereby HMG-CoAreductase in liver in inhibited bymevalonate, the immediate product &cholesterol, the main product of the
pathway (cholesterol metabolite, eg.oxygenated sterol is considered to represstranscription of the HMG-CoA reductasegene
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Many factors influence the cholesterol balance
in tissues: Increase is due to:
uptake of cholesterol-containing
lipoproteins by receptors;uptake of free cholesterol from cholesterol-
rich lipoproteins to the cell membrane;
cholesterol synthesis; andhydrolysis of cholesteryl-ester by the
enzyme cholesteryl ester hydrolase
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Decrease is due to:
efflux of cholesterol from the membrane
to lipoproteins of low cholesterol
potential;
esterification of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT);
and
utilization of cholesterol for synthesis ofother steroids, such as hormones or bile
acids in liver
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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-mediatedreverse transport.
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Cholesterol is transported
between
tissues in plasma lipoproteins
• In human on westernized diets, the total plasma
cholesterol is about 5.2 mmol/L (rising with age & widevariations between individuals)
• Mostly in esterified form & transported in plasma
lipoproteins being the highest in the LDL (or in VLDL if
VLDL is quantitatively more prominent)
• Dietary cholesterol takes several days to equilibrate with
cholesterol in the plasma & several weeks to equilibrate
with cholesterol of the tissues
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Good & bad Cholesterol
and their effect on health
• It is commonly known that a high level of
cholesterol in the blood – hypercholesterolemia –
poses a risk for coronary heart disease (CHD) &
heart attack.
• Cholesterol is insoluble in the blood, it is
transported to and from the cells by carriers
known as lipoproteins
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Low-density lipoprotein (LDL) or “Bad
Cholesterol”
• Is the major cholesterol carrier in the blood iftoo much LDL cholesterol circulates in theblood.
• It can slowly build up in the walls of thearteries feeding the heart and brain. Togetherwith other substances it can form plaque, a
thick, hard deposit that can clog those arteries(a condition known as atherosclerosis)
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High-density lipoprotein (HDL) or “Good
Cholesterol”
• Carries about 1/3 to 1/4 of blood cholesterol
• Experts think HDL tends to carry cholesterol
away from the arteries and back to the liver,where it is metabolized and removed.
• It is believed that HDL can remove excesscholesterol from plaques and therefore slow
their growth. However, while a high level ofHDL decreases the associated risks, a low levelof HDL cholesterol level may increase the
possibility of stroke or heart attack.
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Cholesterol excretion
• Cholesterol must enter the liver & be excretedin the bile as cholesterol or bile acids (salts)
• About 1 g of cholesterol is eliminated from the
body per day. Approx. half is excreted in thefeces after conversion to bile acids, the
remainder is excreted as cholesterol.
• Much of the cholesterol excreted in the bile isreabsorbed & at least some of the cholesterol
that serves as precursor for the fecal sterols is
derived from the intestinal mucosa.
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• Coprostanol is the principal sterol in the feces
(formed from cholesterol by the bacteria in
lower intestine)
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Cholesterol 7α-OH-Cholesterol
Cholyl-CoA
Chenodeoxy-
cholyl-CoA
Taurocholic acid
Glycocholic acid
Deoxycholic acidLithocholic acid
Tauro- & glyco-
Chenodeoxycholic acid
(primary bile acid)
(primary bile acid)
(primary bile acid)
(secondary bile acid) (secondary bile acid)
7α-hydroxylase
Vit. C
(-)
Bile acids
Vit. C defic.
Cholesterol (+)
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Most bile acids return to the liver in the
enterohepatic circulation
• Product of fat digestion including cholesterolare absorbed in the first 100 cm of small
intestinum• Primary & secondary bile acids are absorbed
almost exclusively on the ileum, returning tothe liver by way of portal circulation about 98-
99% of the bile acids secreted into theintestine (called enterohepatic circulation)
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• Perhaps only as little as 400 mg/d escapes
absorption & eliminated in the feces(represent a major pathway for the elimination
of cholesterol)
• About 3-5 g bile salts can be cycled throughthe intestine 6-10 times with only a small
amount lost in the feces each day an
amount of bile acid equivalent to that lost inthe feces is synthesized from cholesterol by
the liver.
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