Cholesterol Synthesis,

transport, and excretion

Benjamin Jose C. Quito, M.D.,

FPCP, FPCC
 Objectives:

• To discuss pathways of cholesterol

synthesis, transport and excretion

• To correlate these biochemical concepts

to everyday practice
 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.
• Cholesterol is precursor of all other
steroids in the body (corticosteroids,
sex hormones, bile acids & vitamin D)

• It is typically a product of animal

metabolism  occurs in food of animal
origin (egg yolk, meat, liver, brain)
• 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.
 Microsome

• A particle in a particulate fraction that is

obtained by heavy centrifugation of broken
cells and consists of various amounts of
ribosomes, fragmented endoplasmic
reticulum, and mitochondrial cristae
 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
 Atherosclerosis Timeline
Complicated
Foam Fatty Intermediate Fibrous Lesion/
Cells Streak Lesion Atheroma Plaque Rupture

Endothelial Dysfunction
From First From Third From Fourth
Decade Decade Decade

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

 Atherosclerosis-Risk factors
• Proven Risk factors for Atherosclerosis:
– Cigarette Smoking
– Hypertension
– Diabetes
– Obesity
– Age
– Male gender
– previous occurrence of CAD
– increased plasma Cholesterol
(principally LDL and Triglycerides)
 Coronary Artery Disease
• a chronic disorder
• the disease typically cycles in and out of clinically
defined phases:
– asymptomatic
– stable angina
– progressive angina
– acute coronary syndrome
unstable angina, NQMI, acute MI
 ATHEROSCLEROSIS
• Coronary Arteries
– Myocardial Infarction
• CNS arteries
– Stroke, Transient Ischemic Attack
• Peripheral circulation
– Intermittent claudication, gangrene
• Kidneys
– Renal artery stenosis
 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-3-
methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation
reactions are required to solubilize the isoprenoid intermediates in the pathway.
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
cholesterol-rich lipoproteins to the cell
membrane;
• cholesterol synthesis;
• 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 acyl-
CoA:cholesterol acyltransferase (ACAT);
• 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 acyl-
CoA:cholesterol acyltransferase, ACAT

3. Regulation of plasma cholesterol levels via

LDL receptor-mediated uptake and HDL-
mediated reverse transport.
 Good and Bad Cholesterols and
their affect on Health.

• It is commonly known that a high level of

cholesterol in the blood –
hypercholesterolemia- poses a risk for
coronary heart disease and 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 one-third to one-fourth of blood
cholesterol
• Experts think HDL tends to carry cholesterol
away from the arteries and back to the liver,
where it is metabolised 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 and excreted in the
bile as cholesterol or bile acids (salts)
• About 1 g cholesterol is eliminated from the body
per day
• Much of cholesterol secreted in the bile is
reabsorbed
• 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)
 Other receptors that promote lipid
loading:
• Macrophage “scavenger” receptors
– Endocytose modified lipoproteins

• Receptors for oxidized LDL or very low-

density lipoprotein (VLDL)
 Formation of the Fatty Streak:
• Monocyte Attachment to the Endothelium
 Formation of the Fatty Streak:
• Monocyte Attachment to the Endothelium

• Migration into the intima

 Formation of the Fatty Streak:
• Monocyte Attachment to the Endothelium

• Migration into the intima

• Maturation to form lipid-laden

macrophages
Monocyte attachment to the endothelium

Endothelial monolayer overlying the intima

contacts blood.
Hypercholesterolemia promotes
accumulation of LDL in the intima.
(yellow spheres)
LDL associate themselves with
constituents of the extracellular matrix
(proteoglycans).
Some LDL undergoes oxidative
modification (darker spheres) which
may trigger a local inflammatory
response, recruiting monocytes
Chemoattractant factors (modified
LDL, cytokines [green spheres]) attract
WBC (monocytes) into the intima
Monocytes become phagocytes which
contain scavenger receptors.
Phagocytes ingest lipids and become
foam cells.
Cytoplasm of foam cells express lipid
droplets.
Smooth muscle cells migrate from the
media, through the internal elastic
membrane, and they accumulate
within the intima
 Formation of the Fatty Streak:
• Monocyte Attachment to the Endothelium

• Migration into the intima

• Maturation to form lipid-laden

macrophages
FOUR STATIN BENEFIT
GROUPS
ASCVD RISK CALCULATOR
ASCVD RISK CALCULATOR
 MODERATE
HIGH INTENSITY STATIN INTENSITY STATIN

• Daily dose lowers • Daily dose lowers

LDL-C by LDL-C by
approximately 50% approximately 30-
50%
• Although diabetic individuals often have
LDL cholesterol levels near the average,
the LDL particles tend to be smaller and
denser, thus more atherogenic.