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].
cholesterol lowering therapies. Current guidelines A recent systematic review [76] 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 [1]. 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 [83]. 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 [77]. 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 [78]: 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 [84]. 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, 1. Greenfeder S. Emerging strategies and agents to lower vs. 23 in the placebo group), achieving a borderline cardiovascular risk by increasing high density lipoprotein statistical significance (p = 0.05). Of note, the cholesterol levels. Curr Med Chem 2009; 16: 144-56.
average age in the SEAS trial was 68 years. 2. Endo A. The discovery and development of HMG-CoA In this setting, beyond the immunomodulatory reductase inhibitors. 1992. Atheroscler Suppl 2004; 5: 67-80.
3. Mascitelli L, Pezzetta F, Goldstein MR. Are statin effects effect of simvastatin which might promote growth mediated through, or in spite of, their cholesterol-lowering increase of occult cancers, it cannot be dismissed the action of ezetimibe which inhibits the 4. Ikonen E. Cellular cholesterol trafficking and compart- absorption of phytosterols and other phytonutrients mentalization. Nat Rev Mol Cell Biol 2008; 9: 125-38.
that are linked to protection against cancer [79]. 5. Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature 2005; 438: 612-21.
6. Kiortsis DN, Filippatos TD, Mikhailidis DP, Elisaf MS, Liberopoulos EN. Statin-associated adverse effects beyond Studies associating statin therapies with muscle and liver toxicity. Atherosclerosis 2007; 195: 7-16.
reductions in bone loss conflict with those reporting 7. Ravnskov U, McCully KS. Review and hypothesis: an association with bone fractures [80]. If statin vulnerable plaque formation from obstruction of vasavasorum by homocysteinylated and oxidized lipoprotein therapies are down regulating lipid trafficking, bone aggregates complexed with microbial remnants and ldl remodelling might be slowed. Osteoclasts, when autoantibodies. Ann Clin Lab Sci 2009; 39: 3-16.
Glyn Wainwright, Luca Mascitelli, Mark R. Goldstein 8. Xia F, Xie L, Mihic A, et al. Inhibition of cholesterol 29. Jeremic A, Jin Cho W, Jena BP. Cholesterol is critical to the biosynthesis impairs insulin secretion and voltage-gated integrity of neuronal porosome/fusion pore. Ultramicroscopy calcium channel function in pancreatic beta-cells.
30. Golomb BA, Evans MA. Statin adverse effects: a review of 9. Sukhija R, Prayaga S, Marashdeh M, et al. Effect of statins the literature and evidence for a mitochondrial mechanism.
on fasting plasma glucose in diabetic and nondiabetic Am J Cardiovasc Drugs 2008; 8: 373-418.
patients. J Investig Med 2009; 57: 495-9.
31. Göritz C, Mauch DH, Nägler K, Pfrieger FW. Role of glia- 10. Szendroedi J, Anderwald C, Krssak M, et al. Effects of high- derived cholesterol in synaptogenesis: new revelations in dose simvastatin therapy on glucose metabolism and the synapse-glia affair. J Physiol Paris 2002; 96: 257-63.
ectopic lipid deposition in nonobese type 2 diabetic 32. Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard patients. Diabetes Care 2009; 32: 209-14.
WR, Albers JJ. Statins of different brain penetrability 11. Ishikawa M, Okajima F, Inoue N, et al. Distinct effects of differentially affect CSF PLTP activity. Dement Geriatr Cogn pravastatin, atorvastatin, and simvastatin on insulin secretion from a beta-cell line, MIN6 cells. J Atheroscler 33. Muldoon MF, Barger SD, Ryan CM. et al. Effects of lovastatin on cognitive function and psychological well- 12. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for 34. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB.
a protective treatment effect in the West of Scotland Randomized trial of the effects of simvastatin on cognitive Coronary Prevention Study. Circulation 2001; 103: 357-62.
functioning in hypercholesterolemic adults. Am J Med 13. Keech A, Colquhoun D, Best J, et al.; LIPID Study Group.
Secondary prevention of cardiovascular events with long- 35. Sparks DL, Sabbagh M, Connor D, et al. Statin therapy in term pravastatin in patients with diabetes or impaired Alzheimer’s disease. Acta Neurol Scand Suppl 2006; 185: fasting glucose: results from the LIPID trial. Diabetes Care 36. Simons M, Schwärzler F, Lütjohann D, et al. Treatment with 14. Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study simvastatin in normocholesterolemic patients with Group. Rosuvastatin to prevent vascular events in men Alzheimer’s disease: A 26-week randomized, placebo- and women with elevated C-reactive protein. N Engl J Med controlled, double-blind trial. Ann Neurol 2002; 52: 346-50.
37. McGuinness B, Craig D, Bullock R, Passmore P. Statins for 15. Simons K, Ikonen E. Functional rafts in cell membranes.
the prevention of dementia. Cochrane Database Syst Rev 16. Brown DA, London E. Functions of lipid rafts in biological 38. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al.; Stroke membranes. Annu Rev Cell Dev Biol 1998; 14: 111-36.
Prevention by Aggressive Reduction in Cholesterol Levels 17. Pike LJ. Rafts defined: a report on the Keystone (SPARCL) Investigators. High-dose atorvastatin after stroke Symposium on Lipid Rafts and Cell Function. J Lipid Res or transient ischemic attack. N Engl J Med 2006; 355: 18. Simons K, Toomre D. Lipid rafts and signal transduction.
39. Goldstein LB, Amarenco P, Szarek M, et al.; SPARCL Nat Rev Mol Cell Biol 2000; 1: 31-9. [Erratum in: Nat Rev Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study.
19. Barenholz Y. Cholesterol and other membrane active sterols: from membrane evolution to “rafts”. Prog Lipid 40. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB.
Statin treatment and the occurrence of hemorrhagic 20. de Meyer F, Smit B. Effect of cholesterol on the structure stroke in patients with a history of cerebrovascular of a phospholipid bilayer. Proc Natl Acad Sci U S A 2009; 41. Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart 21. Salaün C, James DJ, Chamberlain LH. Lipid rafts and the Protection Study Collaborative Group. Effects of cholesterol- regulation of exocytosis. Traffic 2004; 5: 255-64.
lowering with simvastatin on stroke and other major vascular 22. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P.
events in 20 536 people with cerebrovascular disease or other Molecular biology of the cell. Garland Science, 2002.
high-risk conditions. Lancet 2004; 363: 757-67.
23. Waseem TV, Kolos VA, Lapatsina LP, Fedorovich SV.
42. Fitzner D, Schneider A, Kippert A, et al. Myelin basic Influence of cholesterol depletion in plasma membrane protein-dependent plasma membrane reorganization in of rat brain synaptosomes on calcium-dependent and the formation of myelin. EMBO J 2006; 25: 5037-48.
calcium-independent exocytosis. Neurosci Lett 2006; 405: 43. Klopfleisch S, Merkler D, Schmitz M, et al. Negative impact of statins on oligodendrocytes and myelin formation in 24. Pfrieger FW. Role of cholesterol in synapse formation and vitro and in vivo. J Neurosci 2008; 28: 13609-14.
function. Biochim Biophys Acta 2003; 1610: 271-80.
44. Paintlia AS, Paintlia MK, Singh AK, Singh I. Inhibition of rho 25. Mauch DH, Nägler K, Schumacher S, et al. CNS family functions by lovastatin promotes myelin repair in synaptogenesis promoted by glia-derived cholesterol.
ameliorating experimental autoimmune encephalomyelitis.
26. Jang DJ, Park SW, Kaang BK. The role of lipid binding for 45. Trajkovic K, Dhaunchak AS, Goncalves JT, et al. Neuron to the targeting of synaptic proteins into synaptic vesicles.
glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J Cell Biol 2006; 172: 937-48.
27. Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro 46. Harbige LS. Fatty acids, the immune response, and blood-brain barrier transport of 3-hydroxy-3-methylglutaryl autoimmunity: a question of n-6 essentiality and the coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res balance between n-6 and n-3. Lipids 2003; 38: 323-41.
47. Kim N, Stiegler AL, Cameron TO, et al. Lrp4 is a receptor 28. Kandiah N, Feldman HH. Therapeutic potential of statins for Agrin and forms a complex with MuSK. Cell 2008; 135: in Alzheimer’s disease. J Neurol Sci 2009; 283: 230-4.
Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes? 48. Zhang X, Orlando K, He B, et al. Membrane association 69. Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam and functional regulation of Sec3 by phospholipids and DG. Statins and sepsis: multiple modifications at multiple Cdc42. J Cell Biol 2008; 180: 145-58.
levels. Lancet Infect Dis 2007; 7: 358-68.
49. Willmann R, Pun S, Stallmach L, et al. Cholesterol and lipid 70. Monneret G, Venet F. Statins and sepsis: do we really need microdomains stabilize the postsynapse at the to further decrease monocyte HLA-DR expression to treat neuromuscular junction. EMBO J 2006; 25: 4050-60.
septic patients? Lancet Infect Dis 2007; 7: 697-9.
50. Purvin V, Kawasaki A, Smith KH, Kesler A. Statin- 71. Gordon BR, Parker TS, Levine DM, et al. Low lipid associated myasthenia gravis: report of 4 cases and concentrations in critical illness: implications for review of the literature. Medicine (Baltimore) 2006; 85: preventing and treating endotoxemia. Crit Care Med 1996; 51. Cartwright MS, Jeffery DR, Nuss GR, Donofrio PD. Statin- 72. Read TE, Harris HW, Grunfeld C, Feingold KR, Kane JP, associated exacerbation of myasthenia gravis. Neurology Rapp JH. The protective effect of serum lipoproteins against bacterial lipopolysaccharide. Eur Heart J 1993; 14 52. Baker SK, Tarnopolsky MA. Sporadic rippling muscle disease unmasked by simvastatin. Muscle Nerve 2006; 73. Feingold KR, Grunfeld C. Lipoproteins: are they important components of host defense? Hepatology 1997; 26: 1685-6.
53. de Sousa E, Howard J. More evidence for the association 74. McDonald MC, Dhadly P, Cockerill GW, et al. Reconstituted between statins and myasthenia gravis. Muscle Nerve high-density lipoprotein attenuates organ injury and adhesion molecule expression in a rodent model of 54. Oh SJ, Dhall R, Young A, Morgan MB, Lu L, Claussen GC.
endotoxic shock. Shock 2003; 20: 551-7.
Statins may aggravate myasthenia gravis. Muscle Nerve 75. Goldstein MR, Mascitelli L, Pezzetta F. The double-edged sword of statin immunomodulation. Int J Cardiol 2009; 55. Gilhus NE. Is it safe to use statins in patients with myasthenia gravis? Nat Clin Pract Neurol 2009; 5: 8-9.
76. Kuoppala J, Lamminpää A, Pukkala E. Statins and cancer: 56. Colman E, Szarfman A, Wyeth J, et al. An evaluation of A systematic review and meta-analysis. Eur J Cancer 2008; a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA’s spontaneous adverse event 77. Goldstein MR, Mascitelli L, Pezzetta F. Statin therapy in reporting system. Pharmacoepidemiol Drug Saf 2008; 17: the elderly: misconceptions. J Am Geriatr Soc 2008; 56: 57. Goldstein MR, Mascitelli L, Pezzetta F. Dyslipidemia is 78. Rossebo/ AB, Pedersen TR, Boman K, et al.; SEAS a protective factor in amyotrophic lateral sclerosis.
Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359: 58. Lester D. Serum cholesterol levels and suicide: a meta- analysis. Suicide Life Threat Behav 2002; 32: 333-46.
79. Bradford PG, Awad AB. Phytosterols as anticancer 59. Edgar PF, Hooper AJ, Poa NR, Burnett JR. Violent behavior compounds. Mol Nutr Food Res 2007; 51: 161-70.
associated with hypocholesterolemia due to a novel APOB 80. Demer LL. Boning up (or down) on statins. Arterioscler gene mutation. Mol Psychiatry 2007; 12: 258-63.
60. Lalovic A, Levy E, Luheshi G, et al. Cholesterol content in 81. Funk JL, Chen J, Downey KJ, Clark RA. Bone protective brains of suicide completers. Int J Neuropsychopharmacol effect of simvastatin in experimental arthritis. J Rheumatol 61. Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle 82. Sivas F, Alemdarog˘lu E, Elverici E, Kulug˘ T, Ozoran K. Serum SH. Cholesterol reduction and non-illness mortality: meta- lipid profile: its relationship with osteoporotic vertebrae analysis of randomised clinical trials. BMJ 2001; 322: 11-5.
fractures and bone mineral density in Turkish post- 62. Baigent C, Keech A, Kearney PM, et al.; Cholesterol menopausal women. Rheumatol Int 2009; 29: 885-90.
Treatment Trialists’ (CTT) Collaborators. Efficacy and safety 83. Howard-Alpe G, Foëx P, Biccard B. Cardiovascular of cholesterol-lowering treatment: prospective meta- protection by anti-inflammatory statin therapy. Best Pract analysis of data from 90,056 participants in 14 Res Clin Anaesthesiol 2008; 22: 111-33.
randomised trials of statins. Lancet 2005; 366: 1267-78.
84. Danaei G, Ding EL, Mozaffarian D, et al. The preventable 63. Golomb BA, Kane T, Dimsdale JE. Severe irritability causes of death in the United States: comparative risk associated with statin cholesterol-lowering drugs. QJM assessment of dietary, lifestyle, and metabolic risk factors.
64. Zakharova L, Svetlova M, Fomina AF. T cell exosomes induce 85. Kovesdy CP, Kalantar-Zadeh K. Lipids in aging and chronic cholesterol accumulation in human monocytes via illness: impact on survival. Arch Med Sci 2007; 3, 4A: S74- phosphatidylserine receptor. J Cell Physiol 2007; 212: 174-81.
65. Zeiser R, Maas K, Youssef S, Dürr C, Steinman L, Negrin RS. Regulation of different inflammatory diseases byimpacting the mevalonate pathway. Immunology 2009;127: 18-25.
66. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind,randomised placebo-controlled trial. Lancet 2004; 363:2015-21.
67. Peterson MM, Mack JL, Hall PR, et al. Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureusinfection. Cell Host Microbe 2008; 4: 555-66.
68. Goldstein MR, Mascitelli L, Pezzetta F. Methicillin-resistant Staphylococcus aureus: a link to statin therapy? CleveClin J Med 2008; 75: 328-9.


Name ________________________________________________ Single ______ Married ______ Divorced ______ Email ___________________________Social Security Number ____________________ Birthdate ____________ Home Phone ______________________ Cell Phone ______________________Residence Address ____________________________________________________ City _____________________ State __________ Zip _____________

Copyright ©2010-2018 Medical Science