Ams 3 2009.qxp
Cholesterol-lowering therapy and cell membranes. Stableplaque at the expense of unstable membranes?
Glyn Wainwright1, Luca Mascitelli2, Mark R. Goldstein3
1Independent Reader of Research, Leeds, United Kingdom
2Medical Service, Comando Brigata Alpina “Julia”, Udine, Italy
3Fountain Medical Court, Bonita Springs, FL, USA
Comando Brigata Alpina “Julia”Medical Service
Current guidelines encourage ambitious long term cholesterol lowering withstatins, in order to decrease cardiovascular disease events. However, byregulating the biosynthesis of cholesterol we potentially change the form andfunction of every cell membrane from the head to the toe. As research into cellmorphology and membrane function realises more dependencies uponcholesterol rich lipid membranes, our clinical understanding of long terminhibition of cholesterol biosynthesis is also changing. This review of non-cardiovascular research concerning such membrane effects raises importantnew issues concerning the clinical advantages and disadvantages of the longterm use, and broadening criteria, of cholesterol reductions.
Key words: cholesterol, exocytosis, lipid, membrane, statin.
The undoubted commercial success story in modern medicine has been
the creation of that infamous household dietary and medical obsession:‘Cholesterol’. Over the past decade researchers have achieved new insightinto the regulatory relationship between cholesterol and the world of lipidtransport.
A persuasive association of statistics about cardiovascular outcomes
and levels of blood plasma lipids has created a sophisticated range oftherapeutic targets for cholesterol lowering therapies .
Statin drugs are extensively used and are very effective in lowering
serum low-density lipoprotein cholesterol . They have been shown toreduce the incidence of cardiovascular events especially in secondaryprevention, although there is reason to believe that most of their effectsare mediated in spite of their cholesterol lowering action .
De-novo cholesterol, the target of statin therapy, is found in all
membranes and lipid based bodies, where it is now known to be vital totheir proper structure and operation. Ikonen’s excellent review of‘cholesterol trafficking’  summarises the processes and mechanisms bywhich cholesterol contributes to vesicle formation, migrations andmembrane functions throughout the cellular apparatus, and also illustratesthe importance of cholesterol homeostasis. The function and adequacy ofcholesterol in lipid membranes directly influences the production, secretion,delivery and utilisation of every lipoprotein .
Glyn Wainwright, Luca Mascitelli, Mark R. Goldstein
By regulating the biosynthesis of cholesterol we
55 mg per deciliter [interquartile range, 44 to 72
potentially change the form and function of every
membrane from the head to the toe. Statins created
It is intriguing that salutary lifestyle measures,
a potent medical opportunity along with potential
which might exert their beneficial action through
for harm . The past decade of research has
an anti-inflammatory mechanism without a strong
exposed the nature of cholesterol-rich membrane
cholesterol-lowering effect, beyond reducing
rafts, raising fundamental clinical implications in
cardiovascular events and total mortality, reduce
neurology, immunology and all areas where
also the risk of diabetes and other chronic
lipoproteins are created, secreted and utilised. Our
degenerative diseases. This fact may represent
appreciation of cholesterol now extends far beyond
a ‘justification’ not to use a drug in low-risk primary
the statistical link with cardio-vascular outcomes .
prevention populations: lowering cholesterol at theexpense of increasing diabetes might be counter-
Xia et al.
inhibited a late step in the biosynthesis
of de-novo cholesterol in murine and humanpancreatic β cells  and published their findings
The role of cholesterol in cellular function
in 2008. They had previously shown that insulin
became evident with the advent of the lipid raft
secretion was sensitive to the acute removal of
hypothesis . The original lipid raft hypothesis
membrane cholesterol. They now demonstrate that
proposed the existence of assemblies of specific
the depletion of membrane cholesterol impairs
lipids, that compartimentalise the plasma
calcium voltage channels, insulin secretory granule
membrane into functionally distinct areas [15, 16]
creation, and mobilisation and membrane fusion.
involved in protein sorting events in polarized cells.
This paper  clearly demonstrates that a direct
It has now been clarified that lipid rafts are
causal link exists between membrane cholesterol
cholesterol- and sphingolipid-enriched membrane
depletion and the failure of insulin secretion. Their
microdomains that function as platforms that
work is in close accord with data from some statin
concentrate and segregate proteins within the
trials, which also connect cholesterol reduction with
plane of the bilayer ; they are now thought to
increased risk of type 2 diabetes; indeed, statin use
regulate membrane trafficking in both the
has been shown to be associated with a rise of
exocytotic and endocytotic pathways, cell migration,
fasting plasma glucose in patients with and without
and a variety of cell signalling cascades .
diabetes . The underlying mechanisms of the
Lipid rafts consist of both protein and lipid
potential adverse effects of statins on carbohydrate
components existing in continuity with non-raft
homeostasis are complex  and might be related
regions of membrane. Lipid-lipid interactions seem
to the lipophilicity of the statin . Indeed,
to be of fundamental importance to the formation
retrospective analysis of the West of Scotland
of lipid rafts, with cholesterol playing a special role
Coronary Prevention Study (WOSCOPS) revealed
as the ‘glue’ that holds these domains together .
that 5 years of treatment with pravastatin reduced
diabetes incidence by 30% . The authors
depletion in membranes is dramatically illustrated
suggested that although lowering of trigliceride
by the experimental modelling work of de Meyer
levels could have influenced diabetes incidence,
. They were able to demonstrate the
other mechanisms such as anti-inflammatory action
manner in which cholesterol is uniquely able to
might have been involved; however, in the
influence the structure, thickness, permeability,
multivariate Cox model, baseline total cholesterol
deformation and other behaviours of membranes.
did not predict the development of diabetes .
A state of ordered stability is attained in cholesterol-
Furthermore, pravastatin did not decrease diabetes
rich lipid rafts when the level reaches 20-30%
incidence in the LIPID trial which included glucose-
intolerant patients . On the other hand, in the
On the other hand, disorder, weakness and
JUPITER trial (Justification for the Use of Statins in
permeability might be created in cholesterol
Prevention: an Intervention Trial Evaluating
depleted membranes areas: cholesterol depletion
Rosuvastatin), which studied apparently healthy
inhibiting regulated exocytosis is a key discussion
persons without hyperlipidemia but with elevated
point in the review by Salaün et al.
high-sensitivity C-reactive protein levels , the
for molecule, cholesterol can make up nearly half
risk of diabetes was increased by a factor of 1.25
of the cell membrane in lipid raft areas, cholesterol
[95% confidence interval (CI), 1.05 to 1.51] among
typically makes up 20% of total lipid molecules in
individuals receiving rosuvastatin 20 mg daily with
the membrane . Just for example, a relatively
respect to placebo. Strikingly, among persons
small depletion (< 10%) in synaptosomal membrane
assigned to rosuvastatin, the median low density
cholesterol has been shown to be enough to inhibit
lipoprotein (LDL) cholesterol level at 12 months was
the release of a neurotransmitter .
Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes?
relatively younger healthier samples (lovastatin inone, simvastatin in other) showed significant
Nowhere is the impact of cholesterol depletion
worsening of cognitive indices relative to placebo
more keenly studied than in the neurologic arena.
[33, 34]. On the other hand, two trials in Alzheimer
The work of Pfrieger et al
. described the functional
samples (with atorvastatin and simvastatin
role of cholesterol in memory through synapto-
respectively) suggested possible trends to cognitive
genesis . Mauch et al
.  reported evidence that
benefit, although these appeared to dissipate at
cholesterol is vital to the formation and correct
1 year [35, 36]. A recent Cochrane review concluded
operation of neurons to such an extent that neurons
that there is good evidence from randomised trials
require additional sources of cholesterol to be
that statins given in late life to individuals at risk
secreted by glial cells. A recent mini-review by Jang
of vascular disease have no effect in preventing
. describes the synaptic vesicle secretion in
Alzheimer´s disease or dementia . However,
neurons and its dependence upon cholesterol-rich
case reports and case series from clinical practice
membrane areas of the synaptic membrane .
in the real world reported cognitive loss on statins
Furthermore, working on rat brain synaptosomes,
that resolved with discontinuation and recurred
Waseem  demonstrated that a mere 9.3%
decrease in the cholesterol level of the synaptosomal
Evidence from observational data and prestatin
plasma membrane could inhibit exocytosis. These
hypolipidemic randomised trials showed higher
data might be particularly worrisome for lovastatin
hemorrhagic stroke risk with low cholesterol .
and simvastatin which are known to cross the blood
In fact, in the Stroke Prevention with Aggressive
Reductions in Cholesterol Levels (SPARCL) trial as
In fact, the proposed use of statins as a thera-
compared with placebo, the use of high-dose
peutic agent in Alzheimer’s disease (AD) 
atorvastatin was associated with a 66% increase
counters Pfrieger’s evidence . Indeed, a reduc-
in the relative risk of hemorrhagic stroke among
tion in cholesterol synthesis leads to depletion of
the patients receiving the statin drug . In
cholesterol in the lipid rafts – i.e. the de-novo
addition to treatment with atorvastatin, an
cholesterol is required in the neurons for synaptic
exploratory analysis of the SPARCL trial found that
function and also in the neuronal membrane fusion
having hemorrhagic stroke as an entry event, male
sex, and advancing age at baseline accounted for
Cognitive problems are the second most frequent
the great majority of the increased risk of
type of adverse events, after muscle complaints, to
hemorrhagic strokes . However, a sensitivity
be reported with statin therapy  and this has
analysis excluding all patients with a hemorrhagic
speculatively been attributed to mitochondrial
stroke as an entry event in the SPARCL trial found
effects. The central nervous sytem (CNS) cholesterol
that statin treatment was still associated with an
is synthesised in situ and CNS neurons only produce
increased risk of hemorrhagic stroke .
enough cholesterol to survive. The substantial
Furthermore, in a subgroup of patients with
amounts needed for synaptogenesis have to be
a history of cerebrovascular disease enrolled in the
supplemented by the glia cells. Having previously
Heart Protection Study  which did not include
shown that in rat retinal ganglion cells without glia
patients with hemorrhagic stroke, a similar
cells fewer and less efficient synapses could form,
increased risk of hemorrhagic stroke during follow-
Göritz et al
.  indicate that limiting cholesterol
availability from glia directly affects the ability ofCNS neurons to create synapses. They note that
synthesis, uptake and transport of cholesterol
directly impacts the development and plasticity ofthe synaptic circuitry. We note their very strong
The process in which axons are protected by the
implication that local de-novo cholesterol synthesis
myelin secretions of the oligodendrocyte requires
in situ is essential in the creation and maintenance
a specialised cholesterol-rich membrane .
Klopfleisch et al.
 describe experimental in vivo
evidence that new myelin (re-myelination) secretion
cholesterol depletion on synaptogenesis, behaviours
by oligodendrocytes is impaired by statins.
and memory loss for patients undergoing long-term
Whilst they attribute much of this failure to
statin therapy. This is particularly important with
signalling interference, they also prevented
lipophilic statins which easily cross the blood brain
detrimental outcomes in vitro by re-incubating
oligodendrocytes with cholesterol. How long are
The effects of statins on cognitive function and
oligodendrocytes able to repair and maintain myelin
the therapeutic potential of statins in Alzheimer’s
in an environment where cholesterol is depleted?
disease are not clearly understood . Two
It has been argued that statins can prevent de-
randomised trials of statins versus placebo in
myelination  through a pleiotropic anti-
Glyn Wainwright, Luca Mascitelli, Mark R. Goldstein
inflammatory effect and this has led to research on
accidents, and violence [61, 62]. However, statin
its use as a multiple sclerosis therapy.
trials are specifically designed to test drug efficacy,
This would appear to contradict Klopfleisch’s
often with run-in phases, and investigators usually
findings , until you consider that initially there
conduct the studies in groups of patients who have
may be multiple conflicting effects over different
time scales: Possibly the initial inhibiting of an auto-
concomitant medications, and when side effects
immune action associated with a de-myelination
are measured, their seriousness and severity are
and subsequent inhibition of oligodendrocyte
not graded. Indeed, in clinical practice it has been
suggested that severe anger and irritability may
Research is needed to establish whether the
apparent initial slowing of de-myelination in statin
Neural systems have significant vulnerability to
therapy would be followed by a catastrophic failure
cholesterol depletion. First is the reduction in the
of the re-myelination work of oligodendrocyte
synaptic exocytosis and endocytosis of essential
exocytosis  as cholesterol synthesis fails.
signalling lipoproteins; then comes the vulnerability
Furthermore, consideration should be given to the
due to the high dependency of myelination on de-
structural state of membranes involved in any auto-
immune process where a complex interplay ofessential membrane lipids, mediated by cholesterol,
There are many immunologic functions that are
cholesterol-rich lipid rafts. There is an accumulation
Symptoms associated with the malfunctioning
of exosome-sourced cholesterol caused by the
of neuromuscular junction have frequently been
infiltration of activated T lymphocytes into an
reported by patients undergoing cholesterol lowering
atherosclerotic plaque as part of the immune
therapies . A LDL receptor, called Lrp-4,
is secreted by the neuro-muscular junction and it
In fact, statins affect multiple cell populations
forms a complex with agrin which binds the muscle
relevant to the immune response . Although
fibre receptor MuSK [47, 48]. The exocytoses of Lrp4
statins has been rarely associated with autoimmune
and agrin are active transport events, mediated
disorders , the Trial of Atorvastatin in
through a cholesterol-rich lipid membrane. The
Rheumatoid Arthritis (TARA) study showed that
secretion of the trans-membrane MuSK protein also
atorvastatin (40 mg daily for 6 months) mediated
requires a cholesterol-rich membrane raft.
modest but clinically apparent antiinflammatory
There is extensive evidence to suggest that the
effects in patients with rheumatoid arthritis .
depletion of cholesterol in both the synapse and post-
However, the observed clinical efficacy was marginal
in relation to both conventional disease-modifying
membranes areas would cause the failure of MuSK,
Lrp4 and agrin exocytosis . Such a failure would
compounds. Furthermore, statins seem to act in
produce a myasthenic syndrome  with symptoms
a disease-specific manner and are not effective in
similar to those defining myasthenia gravis [51-55]
and amyotrophic lateral sclerosis [56, 57].
Peterson et al
.  describe how the exocytosis
of apolipoprotein B, very-low density lipoprotein
(VLDL) and LDL secretions in skin protects againstStaphylococcus aureus
infection by interfering with
The neurological effects of cholesterol depletion
the quorum sensing receptors which are needed to
can produce a wide range of mental conditions
up-regulate the genes required for invasive
reported to be associated with serum cholesterol
infection. In this context we note a previous letter
depletion. Depression, violent behaviour, homicidal
of Goldstein et al.
 highlighting the possibility
behaviour and suicide are all known associates of
of a link between invasive methicillin resistant
(MRSA) infection and statin therapy, when
In a recent study, cholesterol content was
commenting on recent epidemiological trends.
measured in cortical and subcortical tissue of brains
Although no prospective randomised human trials
from 41 male suicide completers and 21 male
testing the effects of statins in sepsis exist, it has
controls. Violent suicides were found to have lower
been suggested that statins, blocking the
gray matter cholesterol content overall compared
inflammatory response associated with sepsis, might
with nonviolent suicides and controls .
be of potential benefit . However, mounting
Randomised trials with statins have not shown
evidence suggests that the initial and intense
a definite association between cholesterol-lowering
systemic inflammatory response in patients,
treatment and non-illness mortality from suicides,
responsible for organ dysfunction and hypoperfusion
Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes?
is accompanied by an anti-inflammatory process,
depleted of membrane cholesterol, will be restricted
acting in a negative-feedback manner. These
in their ability to absorb old bone matrix, thereby
inhibitory mechanisms could become harmful since
appearing to protect against bone loss . Likewise,
nearly all immune functions are compromised, and
osteoblasts, when depleted of membrane chole-
therefore they may account for the majority of deaths
sterol, will be restricted in their ability to secrete new
after sepsis . Moreover, it has been shown that
mineral matrix into fractures. Interestingly, higher
hypocholesterolemia in critical illness and
total serum cholesterol levels have been shown to
multisystem organ failure correlates with decreased
protect against fractures in post-menopausal women
patient survival rates ; lipoproteins have been
found to bind with and neutralize bacterialendotoxins . Indeed, favorable results of lipid-
infusion therapy have been noted in some animal
connection between endocytosis and exocytosis,
The immunomodulatory action of statins might
cholesterol-rich lipid membranes and the trafficking
also be seen as a double-edged sword because it
of lipoproteins within and between cells is the key
may also hinder the host anti-tumor immune
to understanding the benefits and detriments of
response, therefore increasing cancer risk .
cholesterol lowering therapies. Current guidelines
A recent systematic review  found that
encourage aggressive and long-term cholesterol
statins do not have short-term effects on cancer
lowering with statins, in order to decrease
risk. However, the strength of evidence was weak,
cardiovascular disease events . The main benefits
of this therapy are thought to be due to plaque
randomised trials of short duration and related to
stabilization in the arterial wall . However,
highly select people; thus the extrapolation to
cholesterol lowering alters cell membranes from
patients seen in clinical practice should not be
head to toe, the implication of which may be good,
considered straightforward. In particular, the elderly,
bad or neither. Most importantly, more research is
who have depressed immune functions and are
needed in this field, as wider segments of the
more likely than younger subjects to harbor
population are exposed to aggressive cholesterol
microscopic foci of cancer cells, might be
lowering. This research should answer the question:
particularly subject to adverse outcomes from the
Is it possible, with aggressive cholesterol lowering,
immunosuppressive effects of statin therapy .
to achieve long-term plaque stability and
The results of the Simvastatin and Ezetimibe in
simultaneously maintain cellular membrane
Aortic Stenosis (SEAS) trial have been recently
published : during a follow-up of 52.2 months,
simvastatin and ezetimibe, as compared to placebo,
cholesterol is not a major cause of death at the
did not reduce the composite outcome of combined
population level . Changing our current practice
aortic-valve events and ischemic events in patients
pattern could take many years, but we may one day
with aortic stenosis. However, of more concern, an
prescribe cholesterol-raising medications to certain
excess of incident cancers was observed in the
simvastatin-ezetimibe group, with 105 in that groupas compared with 70 in the placebo group (p
= 0.01). Also, deaths from cancer were more
frequent in the active-treatment group (39 deaths,
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CNPBC General Guidelines for Authorized Parenteral Antibiotic Treatment for Lyme Disease General Approach to Parenteral Antibiotic Treatment for Lyme Disease Using Ceftriaxone, Clindamycin,or Bicillin Appropriate informed consent should be obtained regarding: - controversial aspect of Lyme disease diagnosis and treatment (with reference to opposing views from the Infectious Disease