Lipid Technology September 2008, Vol. 20, No.

9 1

DOI 10.1002/lite.200800053

Nutrition
Why is LDL-cholesterol bad cholesterol?
John C. Stanley
Dr. John C. Stanley writes regularly for this journal on the nutritional aspects of lipids. He is an independent nutrition consultant and a
lecturer in biochemistry at Trinity College and St Hugh's College, Oxford, UK. He can be contacted at: Lincoln Edge Nutrition, The
Cottage, Sleaford Road, Wellingore, Lincoln, LN5 0HR, UK; tel: +44-1522-810131; e-mail: john.stanley@trinity.ox.ac.uk.

Summary
The high circulating LDL-cholesterol levels seen in the inherited disease familial hypercholesterolaemia cause high rates of cardiovascular
disease whereas the low circulating LDL-cholesterol levels following statin treatment cause low rates of cardiovascular disease. This is why
LDL-cholesterol is referred to as bad cholesterol by the media. Atherosclerosis is caused not by native circulating LDL particles but rather
by oxidized LDL particles in the arterial wall. Oxidized LDL particles unlike native particles are taken up by macrophages via scavenger
receptors to form foam cells and are treated as autoantigens by the immune system provoking inflammation. Hence many of the
characteristics of the atherosclerotic plaque including its tendency to rupture and cause thrombosis and heart attacks can be explained in
molecular detail by the effects of oxidized LDL particles.

Introduction disease. As a result dietary recommendations include advice to

reduce intake of saturated fat and increase intakes of monounsa-
As discussed in my last article, the media has taken to referring turated and n-6 polyunsaturated fat in an attempt to reduce risk
to low density lipoprotein (LDL)-cholesterol as bad cholesterol of developing cardiovascular disease. For this and other reasons
and to high density lipoprotein (HDL)-cholesterol as good choles- it is widely believed that high circulating concentrations of LDL-
terol. In my last article I explained why HDL-cholesterol can be cholesterol are bad for cardiovascular health.
considered to be good cholesterol and promised to explain why However, none of the above evidence explains why a high cir-
LDL-cholesterol can be considered to be bad cholesterol in my culating LDL-cholesterol concentration is bad for cardiovascular
next article. health, why HDL-cholesterol and LDL-cholesterol levels have
The circulating LDL-cholesterol concentration is regulated by opposite effects on the risk of developing cardiovascular disease
the activity of the LDL receptor. This protein is found on the sur- or why an essential cellular nutrient such as cholesterol can be
face of all cells and is responsible for taking up LDL-cholesterol bad for health at all. It is the purpose of the present article to
from the circulation. When the activity of the receptor is high, explain why LDL-cholesterol can be considered to be bad for car-
LDL-cholesterol is removed from the circulation at high rates diovascular health.
and as a result circulating concentrations of LDL-cholesterol are
comparatively low. By contrast, when the activity of the receptor
is low, LDL-cholesterol is removed from the circulation at low Atherosclerosis, atherosclerotic plaques and
rates and as a result circulating concentrations of LDL-choles-
cardiovascular disease
terol are relatively high.
There are a number of reasons for believing that a high circu- As observed recently “atherosclerosis involves the formation in
lating concentration of LDL-cholesterol has detrimental effects the arteries of lesions that are characterized by inflammation,
on the health of the cardiovascular system. First, patients with lipid accumulation, cell death and fibrosis” (1). The inside sur-
inherited defects in the LDL receptor, a condition known as face of all arteries is lined with a single cell layer of endothelial
familial hypercholesterolaemia (FH), have very high circulating cells. Beneath this layer lies the intimal layer of the arterial wall
concentrations of LDL-cholesterol and very high rates of cardio- itself, consisting of smooth muscle cells embedded in connective
vascular disease. Second, treatment with statins which are drugs tissue. Atherosclerosis is a disease of the intimal layer of the
specifically designed to competitively inhibit the key enzyme of arterial wall.
cellular cholesterol synthesis result in an adaptive increase in The arterial lesions, otherwise known as atherosclerotic pla-
the activity of the LDL receptor aimed at restoring cellular cho- ques, pass through various stages of complexity beginning with
lesterol levels. As a result, statin treatment results in a fall in cir- the so-called fatty streak and ending in the mature atheroma.
culating cholesterol levels and a reduced risk of developing car- The atherosclerotic plaque consists of a core region surrounded
diovascular disease. Third, dietary saturated fatty acids are by a fibrous cap. The core region consists of foam cells, extracel-
known to raise circulating LDL-cholesterol levels whereas diet- lular lipid some of which may be crystalline cholesterol and deb-
ary monounsaturated or omega-6 (n-6) polyunsaturated fatty ris from dead cells. This is surrounded by a fibrous cap consist-
acids are known to lower them. In addition, epidemiological ing of smooth muscle cells and the fibrous protein collagen. The
studies have demonstrated that the intake of saturated fat is plaque also contains many other types of cell which originate in
associated with a high risk of developing cardiovascular disease the circulation including dendritic cells, mast cells, B cells, nat-
whereas intakes of monounsaturated or n-6 polyunsaturated ural killer T cells, monocytes and monocyte-derived macro-
fats are associated with low rates of developing cardiovascular phages. The presence of so many inflammatory and immune

i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2 September 2008, Vol. 20, No. 9 Lipid Technology

cells in the plaque is one reason for believing that atherosclero- Once inside the arterial wall, monocytes differentiate into
sis is a chronic inflammatory condition. macrophages under the influence of macrophage colony-stimu-
It used to be thought that atherosclerotic plaques cause fatal lating factor (M-CSF). This process of differentiation includes
heart attacks by gradually reducing the diameter of the artery increased expression of scavenger receptors which comprise a
leading to a progressive limitation of blood flow. However, it is large family of at least eight classes of cell surface molecules
now recognised that thrombosis or the formation of a blood clot with the ability to take up oxidised LDL particles (4). The uncon-
is the key event. Rupture of the fibrous cap of the plaque leading trolled uptake of oxidised LDL particles by macrophages results
to thrombosis accounts for two-thirds to three-quarters of fatal in the formation of lipid engorged cells called foam cells which
heart attacks while superficial erosion of the plaque accounts are one of the characteristics of atherosclerotic plaques.
for one-fifth to one-quarter (2). The causes of plaque rupture are
clearly critical in this process and the induction of proteases
which gradually hydrolyse the collagen and weaken the fibrous
cap is emerging as the determining factor. Oxidised LDL as an autoantigen
However, the main question for this article is how high circu-
The idea that atherosclerosis is a chronic inflammatory condi-
lating levels of LDL-cholesterol initiate the process of athero-
tion was revolutionary 20 years ago but has now gained wide-
sclerosis.
spread acceptance. This idea has further evolved recently with
the suggestion that atherosclerosis is at least in part an autoim-
mune condition (5). However, it is not at present clear whether
LDL particle oxidation the immune response is pro- or anti-atherogenic. Indeed, it is
possible that some aspects of the immune response are pro-
The LDL particle is the major cholesterol carrier in the circula- atherogenic while others are anti-atherogenic.
tion. The surface of the LDL particle consists of phospholipids, Migration of T cells into the arterial wall is also mediated by
free cholesterol and apolipoprotein (apo) B100 surrounding a VCAM1. Once inside, T cells undergo activation after interacting
core of cholesterol esters and triacylglycerols. The LDL particle is with antigen presenting cells such as macrophages and dendri-
not prone to oxidation while it is in the circulation. tic cells. Among the antigens presented by these cells to the T
However, once the LDL particle crosses the endothelial cell cells are oxidised LDL particles. This stimulates T cell formation
layer lining the artery it can be oxidised in the subendothelial of pro-inflammatory cytokines including interferon-c (IFNc) and
space (3). This process is somewhat ill-defined but it is assumed tumour-necrosis factor (TNF). These cytokines in turn stimulate
that reactive oxygen species such as superoxide, hydrogen per- macrophage production of proteases which hydrolyse collagen
oxide and hydroxyl radicals produced by the surrounding and inhibit smooth muscle collagen synthesis. Both of these pro-
endothelial cells and smooth muscle cells initiate a lipid peroxi- cesses would be expected to weaken the plaque fibrous cap and
dation chain reaction which results in damage to both the lipid ultimately cause plaque rupture or erosion leading to thrombo-
and protein components of the LDL particle. During this process, sis and heart attack.
lipid hydroperoxides are formed that fragment to reactive alde-
hydes such as malondialdehyde and 4-hydroxynonenal. These
species can then be conjugated to the e-amino groups of lysine
residues in apo B100 and to LDL phospholipids such as phospha- Conclusions
tidylethanolamine and phosphatidylserine. In addition, histi-
It can be concluded that arterial wall oxidized LDL particles and
dine, lysine and proline residues in apo B100 are oxidatively
not circulating native LDL particles promote atherosclerosis.
damaged leading to fragmentation of the apo B100 molecule.
The molecular details of how arterial wall oxidized LDL particles
Clearly the oxidative changes to the LDL particle are complex.
cause the formation of atherosclerotic plaques and how these
However, the important point is that oxidised LDL particles are
plaques rupture to provoke thrombosis and heart attack is
handled differently to native LDL particles in at least two ways.
becoming clearer and clearer. However, what is not clear is why
First, oxidised LDL particles are taken up into cells by scavenger
a high circulating concentration of native LDL particles triggers
receptors rather than LDL receptors. Second, oxidised LDL parti-
the processes of atherosclerosis. The assumption seems to be
cles unlike native LDL particles are treated as autoantigens by
that a high circulating concentration of native LDL particles
the immune system. These differences between the handling of
inevitably leads to a high concentration of arterial wall oxidized
oxidised LDL and the handling of native LDL, account for many
LDL particles. This assumption may turn out to be justified but
of the features of the atherosclerotic plaque.
little if any evidence has been produced to support it.
In addition, the above account of how oxidized LDL particles
damage arterial walls and cause atherosclerosis fails to address
Uptake of oxidised LDL by scavenger receptors one very important area. It is beginning to be appreciated that
processes for repairing arterial walls also exist. Consequently,
Migration of circulating monocytes into the arterial wall is the progression of atherosclerosis may turn out to represent the
mediated by adhesion molecules on the surface of endothelial balance between the processes of damaging and the processes of
cells called vascular cell-adhesion molecule 1 (VCAM1). The repairing arterial walls. Perhaps it is this balance that is altered
expression of VCAM1 and hence the ability of monocytes to in favour of damage by risk factors for cardiovascular disease.
migrate into the arterial wall is highest in areas of the circula- Until the processes of repairing arterial walls are understood,
tion with the greatest turbulence of blood flow. This explains there will still be much to learn about the relationship between
why atherosclerotic plaques have the greatest tendency to form circulating native LDL particles, arterial wall oxidized LDL parti-
in parts of the circulation with the greatest turbulence. cles and the progression of atherosclerosis.

i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.lipid-technology.com

Lipid Technology September 2008, Vol. 20, No. 9 3

References 3. Matsuura, E. et al. (2008) Oxidation of LDL and its clinical

implication, Autoimmun. Rev., 7, 558 – 566.
1. Hansson, G.K. and Libby, P. (2006) The immune response 4. Murphy, J.E. et al. (2005) Biochemistry and cell biology of
in atherosclerosis: a double-edged sword, Nat. Rev. Immu- mammalian scavenger receptors, Atherosclerosis, 182, 1 –
nol., 6, 508 – 519. 15.
2. Libby, P. (2008) The molecular mechanisms of the throm- 5. Nilsson, J. and Hansson, G.K. (2008) Autoimmunity in
botic complications of atherosclerosis, J. Intern. Med., 263, atherosclerosis: a protective response losing control? J.
517 – 527. Intern. Med., 263, 464 – 478.

i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.lipid-technology.com