Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
Essay title: What lines of experimental evidence support the assertion that elevated cholesterol plays a key role in the development of atherosclerosis?
Very h...
What lines of experimental evidence support the asserti on that elevated cholesterol
plays a key role in the development of atherosclerosis?
It is widely believed that elevated cholesterol plays a major role in the development of
atherosclerosis, thereby raising risks of coronary heart diseases (CHD) (referred to as the
lipid hypothesis). However, although many studies show that deposit of cholesterol is a
characteristic feature of atherosclerosis, whether there is a casual relationship between
them remain controversial. In this essay, we focus on the lines of experimental evidences
arguing in favour of the lipid hypothesis.
To begin with, the lipid hypothesis is so widespread because it is supported by a plausible-
sounding pathogenesis mechanism. In the body, cholesterol is transported within
lipoproteins by binding to apolipoproteins, there are several types of lipoproteins including
chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-
density lipoprotein (HDL). It was hypothesized that excess LDL that accumulate in artery
walls is subjected to modifications (oxidation, glycation, enzymatic) which contributes to the
progression of atherosclerosis through activation of endothelial cells and innate immunity.
In contrast, HDL is called the “good cholesterol” because it helps remove other forms of
cholesterol from the bloodstream. As early as the 1850s, cholesterol was identified in
atherosclerotic plaques by Virchow, although he incorrectly understood atherosclerosis as
an active process of tissue inflammation instead of the deposition of fatty materials. Later in
1914, Anitchkow with Russian colleagues demonstrated that cholesterol alone caused
atheromatous changes in the vascular wall. His classic experiment involved feeding rabbits
with purified cholesterol dissolved in sunflower oil, or only sunflower oil in the control
group. He observed vascular lesions closely resembling those of human atherosclerosis in
the cholesterol over-fed rabbits whereas the control group did not develop lesions, he later
also showed that the amount of cholesterol consumed by the rabbits is directly proportional
to their severity of atheroma formation. However, similar findings cannot be replicated in
other animals like rats or dogs, we now know that carnivores are capable of efficient
cholesterol metabolism so blood cholesterol does not reflect their dietary cholesterol
intake. Despite the criticism, cholesterol-fed rabbit has been a commonly used model for
atherosclerosis research.
A couple decades later, Brown and Goldstein published a Nobel prize winning paper that
uncovers the pathogenesis of familial hypocholesterolemia (FH). FH is characterized by high
blood cholesterol levels, specifically very high levels of LDL, and early heart attacks. Their
previous work reported failure of lipoproteins in suppressing 3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA) reductase activity in FH patients, HMG CoA reductase is known to
catalyse cholesterol production in rat livers and is inhibited by ingested cholesterol via a
negative feedback loop. In 1974, they showed that FH homozygous cells lack high affinity
binding sites for LDL when they studied binding of radioactive 125I-LDL to monolayers of
cultured fibroblasts. Their discovery proved the existence of LDL receptors and that their
deficiency in FH patients due to genetic mutations prevent uptake of cholesterol into cells,
so HMG CoA activity in FH patients is not suppressed in the absence of intracellular
cholesterol, resulting in overproduction of cholesterol. Yet, their findings lead to high
amounts of skepticism, especially among lipid biologists, these detractors argue that only a
small fraction of LDL was bound to cells in the experiment and that the non-specific
stickiness of LDL to a variety of surfaces may explain the binding without the need of the
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