Disorders of Lipid Metabolism 2:

atherosclerosis, dyslipidemia and

insulin resistance, cholesterol reduction

A/P Dr Tony Ng
Dept of Biomedical Science
UTAR Kampar

1
Lesson Outcomes
At the end of this lesson, the student
should be able to:

1. explain the relationship between insulin resistance

and hypertriglyceridemia

2. describe manipulation of the extrahepatic circulation

to reduce plasma cholesterol

3. state the sequence of events leading to the formation

of the atherosclerotic lesion in the arterial
endothelium.

2
Explain the
Hypertriglyceridemia
associated with Insulin
Resistance

3
 1. FFAs can either be
oxidized in the
mitochondria to form
ATP or esterified to
produce TAG for storage
or incorporation into
VLDL particles.
2. In liver,
hyperinsulinemia
induces activation of
3. FFAs entering the liver from
lipogenic genes: SREBP-
the periphery, as well as those
1c and ChREBP
derived from de novo
expression, leading to the
lipogenesis, will be
transcriptional activation
preferentially esterified to
of all lipogenic genes.
triglycerides.
4
4. Overproduction of hepatic VLDL leads to hypertriglyceridemia.
5
RECAP!!

Their amphipathic nature

enables bile acids to carry out
two important functions:
1. Emulsification of lipid
aggregates

2. Solubilisation and
transport of lipids in an
aqueous environment
6
 Enterohepatic circulation of
A FAT TALE bile acid/sterols
Stomach
LIVER
*

Pancreas
Short-chain
*
fatty acids
transported *
by portal
system to
*
liver *
*

*
7
8
Small, dense LDL particles
A growing body of evidence suggests that LDL
particles that are small and dense are more
atherogenic than those which are large and less
dense.
Small, dense LDL particles are found in association
with high triglycerides and low HDL.

The small, dense LDL phenotype rarely occurs

as an isolated disorder. It is most frequently
accompanied by hypertriglyceridemia, reduced
HDL cholesterol levels, abdominal obesity,
insulin resistance and by a series of other metabolic
alterations predictive of an impaired endothelial
function and increased susceptibility to thrombosis. 9
10
11
LDL particles
LDL subtype patterns
LDL particles vary in size and density, and studies
have shown that a pattern that has more small dense
LDL particles, called Pattern B, equates to a higher
risk factor for CHD than does a pattern with more of
the larger and less dense LDL particles (Pattern A).
This is because the smaller particles are more easily
able to penetrate the artery endothelium.
In the Physicians Health Study, USA: LDL particle-
size profile of subjects divided into five groups
(quintiles). The lowest quintile--those with the
smallest and most dense LDL particles--had more
than three times the risk of heart attack as the
quintile with the largest LDL particles. 12
 Tocotrienols inhibit LDL oxidation,
endothelial monocyte adhesion, and
expression & activation of CAMs
LDL
Arterial lumen Monocyte
inhibit Adhesion
Expression &
Endothelium activation of CAMs

LDL
T3
Free inhibit Phagocyte
Phagocyte
radicals

LDL- LDL-
oxidised oxidised

Tocopherols Foam cell

(inhibit oxidation of Fatty streaks
LDL)
Reduction of plasma
cholesterol levels

14
15
Palm- tocotrienols
have a statin-like
cholesterol-lowering
action
Tocotrienols
inhibit rate-limiting step in
cholesterol biosynthesis

HMG CoA -------> -------> Cholesterol

HMG CoA
reductase
PUFA from vegetable oils: Linoleic acid (18:2, -6)
content of some common vegetable oils

Sunflower oil

Corn oil

Soybean oil

Canola oil

Palm olein

0 10 20 30 40 50 60 70

LA (%)
Predictive equations of Keys, Hegsted

Used to predict changes in serum TC

brought about by changes in dietary fats.

Equations useful, but have limitations!

1
TC = 2.74 S - 1.31 P + 1.5Z [Keys et al., 1965]

= 1.35 (2S - P) + 1.5Z

2
TC = 8.45 S14 + 2.12 S16 - 1.87 P+
5.64 C - 6.24 [Hegsted, 1965]
 O2 is essential Natural defences are
imperfect; limit the
to human life. harm caused by O2 but
Yet, paradoxically, do not eliminate it
aerobic metabolism completely.
gives rise to harmful O2-induced damage to
by-products (=free body tissues accumulate.
radicals, ROS) which “Oxidative
constantly threaten stress”
Ageing + Degenerative
our well-being.
diseases of ageing
Powerful natural (incld. CVD, cancer, cataracts,
defence mechanisms decline in immune system &
that minimise the nervous system)
toxic effects of O2.
Fact: Natural substances protect our
body against the effect of free radicals,
molecules produced when you break down
food or are exposed to environmental
factors, tobacco smoke and radiation.
 Potentially harmful effects of O2 due to the
formation & activity of reactive O2 species
acting as OXIDANTS, many of which are
FREE RADICALS
SOURCES OF OXIDANTS/ ANTIOXIDANTS/
FREE RADICALS DEFENCES
Exercise Vitamin E
Inflammation Vitamin C
Ischaemia/reperfusion Beta-Carotene
Mitochondria Other carotenoids
Xanthine oxidase Superoxide dismutase
Cigarrete smoke GSH peroxidase
Air pollutants Catalase
Radiation, UV Glutathione, Se
High PUFA intake Ubiquinol, Uric acid
Carcinogens Phenolic acids,
Ozone Polyphenols, Catechins
Can antioxidants
(esp. Vit. E) prevent/
slow down ageing?
 Dr. Lester Packer, is the world’s
foremost antioxidant research
scientist. He is a senior scientist at the
prestigious Lawrence Berkeley Laboratory,
and Head of the Packer Lab at the University
of California, where he has been a professor
for 35 years.

Yes, says the

“guru” of
antioxidant
research!
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