You are on page 1of 43

Cholesterol Synthesis, transport, and

excretion

Abdul Salam M Sofro


Faculty of Medicine
YARSI University

Learning objectives
By the end of lectures, students are
expected to understand:
The process of cholesterol synthesis
and catabolism
Cholesterol transport in blood
circulation & excretion

Ibu S usia 42 th mengeluh pada dokter


keluarganya bahwa sejak beberapa
bulan 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, tetapi
kadar senyawa-senyawa lipid tersebut
belum kembali normal.

Kasus

Photo by: Lev Olkha

Introduction
Cholesterol present in tissue & in plasma
lipoproteins 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 eliminated
from the body in the bile as cholesterol or
bile salts

Slightly less than half of the cholesterol in


the body derives from biosynthesis de novo.
Biosynthesis in the liver accounts for
approximately 10%, and in the intestines
approximately 15%, of the amount produced
each day.
Cholesterol synthesis occurs in the cytoplasm
and microsomes from the two-carbon
acetate group of acetyl-CoA.

http://www.gugulipid.com/mechan.htm

Lipid Structure
Cholesterol
HO

Fatty Acids

HO

Triglycerides

COOH

COO

COOH

COO

COOH

COO

Phospholipid: Lecithin
COO

Glycerol

HO
HO

COO

OPOO

Biomedical importance
Cholesteryl ester is a storage form of cholesterol
found in most tissues
It is transported as cargo in the hydrophobic core
of lipoprotein
LDL is the mediator of cholesterol & cholesteryl
ester uptake into many tissues
Free cholesterol is removed from tissues by HDL
and transported to liver for conversion to bile
acids (cholesterol is major constituent of
gallstones)
Cholesterol plays major role in the genesis of
atherosclerosis

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 three
methyl groups

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-3methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation
reactions are required to solubilize the isoprenoid intermediates in the pathway.

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

17,400 mg/day

Plant sterols compete


For cholesterol here

Stage 5
The conversion of lanosterol to
cholesterol

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.

Regulation of HMG-CoA reductase:


Reduced activity in fasting animals
(reduced synthesis of cholesterol during
fasting)
Feedback mechanism whereby HMG-CoA
reductase in liver in inhibited by
mevalonate, the immediate product &
cholesterol, the main product of the
pathway (cholesterol metabolite, eg.
oxygenated sterol is considered to repress
transcription of the HMG-CoA reductase
gene

Many factors influence the cholesterol balance


in tissues:
Increase is due to:
uptake of cholesterol-containing
lipoproteins by receptors;
uptake of free cholesterol from cholesterolrich lipoproteins to the cell membrane;
cholesterol synthesis; and
hydrolysis of cholesteryl-ester by the
enzyme cholesteryl ester hydrolase

Decrease is due to:


efflux of cholesterol from the membrane
to lipoproteins of low cholesterol
potential;
esterification of cholesterol by acylCoA:cholesterol acyltransferase (ACAT);
and
utilization of cholesterol for synthesis of
other steroids, such as hormones or bile
acids in liver

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 acylCoA:cholesterol acyltransferase, ACAT
3. Regulation of plasma cholesterol levels via LDL
receptor-mediated uptake and HDL-mediated
reverse transport.

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 & wide
variations 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

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

Low-density lipoprotein (LDL) or Bad


Cholesterol
Is the major cholesterol carrier in the blood if
too much LDL cholesterol circulates in the
blood.
It can slowly build up in the walls of the
arteries feeding the heart and brain. Together
with other substances it can form plaque, a
thick, hard deposit that can clog those arteries
(a condition known as atherosclerosis)

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 excess
cholesterol from plaques and therefore slow
their growth. However, while a high level of
HDL decreases the associated risks, a low level
of HDL cholesterol level may increase the
possibility of stroke or heart attack.

Cholesterol excretion
Cholesterol must enter the liver & be excreted
in 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 the
feces after conversion to bile acids, the
remainder is excreted as cholesterol.
Much of the cholesterol excreted in the bile is
reabsorbed & at least some of the cholesterol
that serves as precursor for the fecal sterols is
derived from the intestinal mucosa.

Coprostanol is the principal sterol in the feces


(formed from cholesterol by the bacteria in
lower intestine)

Vit. C

7-OH-Cholesterol

Cholesterol

7-hydroxylase

Cholesterol

Taurocholic acid
(primary bile acid)

(+)

(-)
Bile acids
Vit. C defic.

Cholyl-CoA

Chenodeoxycholyl-CoA

Glycocholic acid
(primary bile acid)

Tauro- & glycoChenodeoxycholic acid


(primary bile acid)

Deoxycholic acid
(secondary bile acid)

Lithocholic acid
(secondary bile acid)

Most bile acids return to the liver in the


enterohepatic circulation
Product of fat digestion including cholesterol
are absorbed in the first 100 cm of small
intestinum
Primary & secondary bile acids are absorbed
almost exclusively on the ileum, returning to
the liver by way of portal circulation about 9899% of the bile acids secreted into the
intestine (called enterohepatic circulation)

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 through
the intestine 6-10 times with only a small
amount lost in the feces each day an
amount of bile acid equivalent to that lost in
the feces is synthesized from cholesterol by
the liver.