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 [1].
Statin drugs are extensively used and are very effective in lowering serum low-density lipoprotein cholesterol [2]. 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 [3].
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’ [4] 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 [5].
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 [6]. 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 [7]. 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 [8] 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 [15]. 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 [8] 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 [17]; 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 [18]. diabetes [9]. 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 [10] and might be related regions of membrane. Lipid-lipid interactions seem to the lipophilicity of the statin [11]. 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 [19].
that 5 years of treatment with pravastatin reduced diabetes incidence by 30% [12]. 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, et al. [20]. 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 [12].
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 [13]. 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. [21]. Molecule high-sensitivity C-reactive protein levels [14], 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 [22]. 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 [23].
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 [24]. Mauch et al. [25] 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 et al. describes the synaptic vesicle secretion in Alzheimer´s disease or dementia [37]. However, neurons and its dependence upon cholesterol-rich case reports and case series from clinical practice membrane areas of the synaptic membrane [26].
in the real world reported cognitive loss on statins Furthermore, working on rat brain synaptosomes, that resolved with discontinuation and recurred Waseem [23] 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 [30].
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) [28] atorvastatin was associated with a 66% increase counters Pfrieger’s evidence [24]. 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 [38]. 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 [39]. However, a sensitivity be reported with statin therapy [30] 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 [40].
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 [41] 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. [31] 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 [42].
Klopfleisch et al. [43] 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 [28]. Two It has been argued that statins can prevent de- randomised trials of statins versus placebo in myelination [44] 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 [43], 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 [45] 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 [30]. 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 [65]. 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 [30], 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 [66].
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 [49]. Such a failure would compounds. Furthermore, statins seem to act in produce a myasthenic syndrome [50] 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. [67] 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. [68] 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 [60].
be of potential benefit [69]. 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 [81]. 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 [70]. 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 [71]; lipoproteins have been found to bind with and neutralize bacterialendotoxins [72]. 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 [75].
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Source: http://www.lizscript.co.uk/Glyn/AMS01.pdf