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The High- CHolesterol Paradox (full essay)

The Paradox

Being told you have ‘high cholesterol’ is commonly taken as a sign of an unhealthy destiny. Research suggests that for many elderly people the news that they have ‘high cholesterol’ is more often associated with good health and longevity1.

For over 50 years this has been a paradox, the ‘High-Cholesterol Paradox’. What is really going on?


Hypothesis becomes Dogma

In the 1950s the prestigious American MD, Dr Ancel Keys2, supported a popular theory that heart disease was caused by dietary Fats and Cholesterol (Lipids) circulating in the blood. In 1972 a British Professor, Dr John Yudkin3, published a book called ‘Pure, White and Deadly’ which proposed over-consumption of refined sugar as the leading cause of diabetes and heart disease. The science was contested by ‘interested parties’, and the matter was resolved by ‘government decree’ in a US Senate report. On Friday January 14th 1977, Senator George McGovern’s Senate Select Committee on Nutrition and Human Needs published ‘Dietary Goals for the United States’.

This document sided heavily with Dr Keys’ lipid theory. Thus ‘hypothesis became dogma’, without the benefit of scientific proof. The McGovern report recommended that we consume more carbohydrates (sugar generating foods) with more limited amounts of fats, meat and dairy. Since the 1970s there has been a rise in the use of High-Fructose Corn Syrups in processed food, and the introduction of low-fat foods which tend to have added sugar to make them attractive to eat. 

Until the 1970s there had been a small but consistent percentage of overweight and obese people in the population.  By the 1980s obesity rates had begun to climb significantly. This sudden acceleration of obesity is very closely associated with the adoption of new high-sugar, low-fat formulations in processed foods - the consequences of the McGovern report recommendations being adopted around the world.

Advice to reduce our intake of saturated fats, obtained from meat and dairy, caused a rise in the use of plant based oils and so-called ‘vegetable fats’. This was misleadingly promoted as healthy.  The biochemical destiny of dietary ‘Saturated Fat’ is not the same as that of excess ‘Carbohydrates and Sugars’.

Fats do not cause obesity or disease. It is the excess sugars (glucose and fructose - High Fructose Corn Syrup HFCS) which create abdominal obesity4.

The erroneous idea, and fear, of artery blocking fats was exploited to market fat substitutes. Invite anyone talking about ‘artery blocking fats’ to hold a pat of butter in a closed fist. As the butter melts and runs out between their fingers, ask ‘How do fats, which are evolved to be fluids at body temperature, block the vascular ‘pipes’ in our bodies?’ 

Plant oils are not the natural lipids for maintaining healthy human or animal cell membranes.  Animal sourced fats, and essential fatty acids (EFA), are identical to those we require for the maintenance of the healthy human body.

Let us explore some more big anomalies in the last 40 years of dietary health guidance.

Good Cholesterol? Bad Cholesterol? Spot the Difference?

All biochemists can confirm that all cholesterol molecules throughout the known universe are identical in every respect. So how can there be ‘good’ or ‘bad’ cholesterol. It is now possible to frighten people with unscientific descriptions like ‘Good’ and ‘Bad’ when talking about cholesterol.

This single misleading description may have prevented a whole generation from knowing the true causes of the very real disturbance in the levels of fatty nutrients (Lipids) circulating in our blood4.

Healthy Lipids

If the total blood serum cholesterol (TBSC) is high and the organs are getting enough lipids, the blood lipid circulation is healthy.  The large parcels of fatty nutrients (LDL lipids) sent by the liver are consumed by our organs (receptor-mediated endocytosis) and the smaller fatty wrappers and left-over lipids (HDL Lipids) return to the liver. The Fatty Nutrients (LDL) and the recycled lipids (HDL) are in balance. Such a healthy-lipid ‘High-Cholesterol’ person is well nourished and likely to have a long and healthy life.

Damaged Lipids

If the total blood serum cholesterol is high but the fatty nutrient droplets (LDLs) have sugar-damaged labels, the organs are unable to recognise and feed on them. The supply of fatty nutrients to organs is broken.  

The liver continues to supply fatty nutrients (albeit with damaged LDL labels), but the organs’ receptors are unable to recognise them. The organs thus become starved of their fatty nutrients. Like badly labelled parcels in a postal service, the sugar-damaged lipids build up in the blood (raised LDL) and fewer empty wrappers are returned to the liver (low HDL).

LDL (erroneously called ‘bad’ cholesterol) is raised in the blood, awaiting clearance by the liver. There is less HDL (erroneously called ‘good’ cholesterol) being returned by the organs.

High Cholesterol (high levels of total blood serum cholesterol TBSC) when caused by damage to the LDL lipid parcels is a sign that lipid circulation is broken. These fats (LDL) will be scavenged to become visceral fats, deposited around the abdomen. This type of damage is associated with poor health.

So it really doesn’t matter how high your total blood serum cholesterol (TBSC) is. What really counts is the damaged condition of the blood’s fatty nutrient parcels (LDL lipids). In our research review of metabolic syndromes4 (e.g. diabetes, heart disease, obesity, arthritis and dementia) we explained that the major cause of lipid damage was sugar-related.

Sugar Damage (AGEs)

The abbreviation AGE (Advanced Glycation End-product) is used to describe any sugar-damaged protein.  As we age, excessive amounts of free sugars in the blood5 may eventually cause damage quicker than the body can repair it.  The sugars attach by a chemical reaction and the sugar called fructose is known to be 10 times more reactive, and therefore more dangerous than our normal blood sugar (glucose). Since the 1970s we have been using increasing quantities of refined fructose (from high-fructose corn syrup). Its appealing sweetness, and ability to suppress the ‘no longer hungry’ receptor6 (ghrelin receptor) is driving excessive food intake.  Its ability to damage our fatty nutrients and lipid circulation is also driving waist-line obesity and its associated health problems4,7.

Checking for Damage in our Lipids

There is a ‘simple to administer’ commonly available blood test used to check for sugar-damage.  It is used to check the proteins in the blood of people who are diabetic or at risk of becoming diabetic. It tests for Glycated Haemoglobin (HbA1c) by counting the proportion of damaged molecules (per 1000) of Haemoglobin protein in the blood (mmol/mol). Researchers looking at ways of testing for damage to lipids, have found that sugar-damaged blood protein test (HbA1c), presents a very reasonable approximation of the state of sugar-damage in the blood lipids. Until there is a good general test for sugar-damage in blood lipids, this test (HbA1c) could be a sensible surrogate. This is a better way of assessing health than a simple cholesterol test (TBSC).

Improved sugar-damaged blood protein (HbA1c) scores in diabetic patients is accompanied by improvements in their lipid profiles. This could be very useful to anyone wanting to improve health outcomes by managing lifestyle and nutrition.

Clinical Consequences of Lowering Cholesterol

In 2008 Dr Luca Mascitelli asked me to examine a paper by Xia et al8. It was very interesting to note that lowering cholesterol by as little as 10% (molecular in cell walls) in the pancreas (pancreatic beta-cells) prevented the release of insulin (cholesterol-mediated exocytosis).  This paper described a mechanism by which ‘cholesterol lowering drugs’ directly cause diabetes. It was known that in statin drug trials which looked at glucose (blood sugar) control there was poor blood-sugar control in the statin user groups.  Since 2011 the USA government (FDA) required statins to carry a warning about the risk of causing diabetes9.

Memories are made of this – Cholesterol

The healthy human brain may only be 5% of body weight but it requires over 25% of the body’s cholesterol. The nervous system uses huge quantities of cholesterol for insulation, protection and structure (myelin).  F W Pfrieger et al.10 have shown that the formation of the memory (synapses) is dependent on good supplies of cholesterol. 

Post-mortem studies show that depleted cholesterol levels in the cerebrospinal fluids are a key feature of dementias. It was also reported that behavioural changes and personality changes are associated with low levels of cerebrospinal cholesterol.

In another review paper on Dementia we commented extensively on the damage done by fructose and the depletion of cholesterol availability. Low cholesterol levels in the nervous system are not conducive to good mental health.

Consequences of Lowering Cholesterol

Drug treatments which lower cholesterol are acknowledged to cause adverse side-effects (ADRs) in at least 10% of Statin users11. This figure may be as high as 30%.

Conservative estimates indicate that in at least 1% of patients the side-effects are serious enough to be life threatening (e.g. Rhabdomyelitis, Dementia, Behavioural Disorders and Violence).

Our review12 found that cholesterol lowering therapies were implicated in:

·         Damage to muscles (including the heart) and exercise intolerance13

·         Increased risk of Dementias (Impaired Synaptogenesis and Neuro-transmission)14

·         Failure of Myelin Maintenance (Multiple Sclerosis  Risks)15

·         Neuro-muscular problems, aches and pains (Amyotrophic Lateral Sclerosis)16

·         Diabetes  (Insulin release inhibited)8

·         Poor Maintenance of Bones and Joints

·         Suppression of protective skin secretions (Apo-B)  and  increased MRSA infection17

Why would anyone want to lower cholesterol?

What is needed is a lowering of damage to lipids  - caused by sugar.


1.            Weiss, A., Beloosesky, Y., Schmilovitz-Weiss, H., Grossman, E. & Boaz, M. Serum total cholesterol: A mortality predictor in elderly hospitalized patients. Clin. Nutr. Edinb. Scotl. 32, 533–537 (2013).

2.            Mancini, M. & Stamler, J. Diet for preventing cardiovascular diseases: light from Ancel Keys, distinguished centenarian scientist. Nutr Metab Cardiovasc Dis 14, 52–7 (2004).

3.            Yudkin, J. Pure, white and deadly: how sugar is killing us and what we can do to stop it. (2012).

4.            Seneff, S., Wainwright, G. & Mascitelli, L. Is the metabolic syndrome caused by a high fructose, and relatively low fat, low  cholesterol diet? Arch. Med. Sci. AMS 7, (2011).

5.            Bierhaus, A., Hofmann, M. A., Ziegler, R. & Nawroth, P. P. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 37, 586–600 (1998).

6.            Lindqvist, A., Baelemans, A. & Erlanson-Albertsson, C. Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul. Pept. 150, (2008).

7.            Seneff, S., Wainwright, G. & Mascitelli, L. Nutrition and Alzheimer’s disease: the detrimental role of a high carbohydrate diet. Eur. J. Intern. Med. 22, 134–140 (2011).

8.            Xia, F. et al. Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells. Endocrinology 149, 5136–45 (2008).

9.            FDA publication. FDA Expands Advice on STATIN RISKS. (2014). at <>

10.          Pfrieger, F. W. Role of cholesterol in synapse formation and function. Biochim Biophys Acta 1610, 271–80 (2003).

11.          Roger Vadon (Producer). BBC File on 4 Statins. (2008).

12.          G Wainwright, L Mascitelli & M Goldstein. Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes? Arch. Med. Sci. 5, 289–295 (2009).

13.          Hall, J. B. Principles of Critical Care  - Rhabdomyolysis and Myoglobinuria. (McGraw Hill 1992, 1992).

14.          Mauch, D. H. et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–7 (2001).

15.          Klopfleisch, S. et al. Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo. J Neurosci 28, 13609–14 (2008).

16.          Goldstein, M. R., Mascitelli, L. & Pezzetta, F. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 71, 956; author reply 956–7 (2008).

17.          Goldstein, M. R., Mascitelli, L. & Pezzetta, F. Methicillin-resistant Staphylococcus aureus: a link to statin therapy? Cleve Clin J Med 75, 328–9; author reply 329 (2008).


The ‘High Cholesterol’ Paradox

Neurons and Dementia

(a) An activated insulin receptor stimulates aerobic oxidation of glucose

(b) Reactive Oxygen Species (ROS) released by excessive overrun of  aerobic oxidation due to low membrane cholesterol allowing ion leakages through  cell membranes (Activation Potential leaks - Runaway Burn!)

(c) ROS stimulate  protective Amyloid-beta protein Aβ production  to plug the holes left by depleted cholesterol in the cell’s membranes. Aβ made in theEndoplasmic Reticulum ER and Golg Apparatuesi;

(d) Aβ also protectively suppresses  he insulin receptor stimulus;

(e) Aβ throttles back on the neuron’s glucose transport (GLUT3);

(f) Aβ substitutes for depleted  cholesterol assisting membrane integrity, reducing Activation Potential ion leakage and Runaway burn.

(g) Aβ plaques accumulate  with ROS induced neuron death (apoptosis)

(h) Raised insulin levels reduces Insulin Destroying Enzyme (IDE) availability for normal Aβ-plaque removal. IDE is a general pupose protease but perhaps insulin distracts it from amyloid clean-up.

Click on text for link to free .pdf download

Related references:

[60] Hirsch-Reinshagen V, Burgess BL, Wellington CL. Why lipids are important for Alzheimer disease?Mol Cell Biochem 2009;326:121–9.

[61] Jiang Q, Lee CYD, Mandrekar S, et al. ApoE promotes the proteolytic degradation of Aβ.Neuron 2008;58:681–93.

[62] Koistinaho M, Lin S, Wu X, et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-βpeptides. Nat Med 2004;10:719–26.

[63] Bishop T, St-Pierre J, Brand MD. Primary causes of decreased mitochondrial oxygen consumption during metabolic depression in snail cells. Am J Physiol Regul Integr Comp Physiol 2002;282:R372-82

[64] Zhao W, De Felice FG, Fernandez S, et al. Amyloid-β oligomers induce impairment of neuronal insulin receptors.FASEB J 2008;22:246–60.

[65] Storozhevykh TP, Senilova YE, Persiyantseva NA, Pinelis VG, Pomytkin IA. Mitochondrial respiratory chain is involved in insulin-stimulated hydrogen peroxide production and plays an integral role in insulin receptor autophosphorylation in neurons.BMC Neurosci 2007;8:84.

[66] Goldstein BJ, Mahadev K, Wu X, Zhu L, Motoshima H. Role of insulin-induced reactive oxygen species in the insulin signaling pathway.Antioxid Redox Signal 2005;7:1021–31.

[67] Miller BC, Eckman EA, Sambamurti K, et al. Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci USA2003;100:6221–6.

[68] Niwa Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C. Aβ-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 2001;281:H2417–24.

[69] Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP. Amyloid-β-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation.J Neurosci 1997;17:1046–54.

[70] Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D. Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid-β-peptide.Am J Physiol Heart Circ Physiol2001;281:H2417–24.

[69] Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP. Amyloidβ-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation.  J Neurosci 1997;17:1046–54.

[70] Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D. Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid-β-peptide.   Biochim Biophys Acta 2000;1502:145–5

Update of notes in our original paper

Cholesterol Synthesis via the Mevalonate Metabolic Pathway, the target of statin therapy, is found in all membranes and lipid based bodies, where it is now known to be vital to their proper structure and operation. Ikonen’s excellent review of ‘cholesterol trafficking’ [4] summarises the processes and mechanisms  by which cholesterol contributes to vesicle formation, migrations and membrane functions throughout the cellular apparatus, and also  illustrates the importance of cholesterol homeostasis. The function and adequacy of  cholesterol in lipid membranes directly influences the  production, secretion, delivery and utilisation of every lipoprotein, neurotransmitter, and transport vesicle. [5]. 

By regulating the biosynthesis of cholesterol we potentially change the  form and function of every  cell membrane from the head to the toe. Statins  created a potent medical opportunity along with a huge potential for harm [6].  The past decades of research have revealed the fabulous functionality of cholesterol-rich  membrane rafts, raising fundamental clinical implications in neurology,  immunology and all areas where lipoproteins are created, secreted and  utilised. Our appreciation of cholesterol now extends far beyond the  statistical (not causal) link with cardio-vascular outcomes [7].

We are now realizing that the intricate connection between endocytosis  and exocytosis, cholesterol-rich lipid membranes and the trafficking of  lipoproteins within and between cells is the key to understanding the  accumulating detriments of cholesterol lowering therapies. Current  guidelines encourage aggressive and long-term cholesterol lowering  with statins, in order to decrease cardiovascular disease events [1]. The  main benefits of this therapy are thought to be due to plaque stabilization in the arterial wall [83]. However, cholesterol lowering alters  cell membranes from head to toe, the implication of which are likely to be  unhelpful for most patients. Most importantly, more research is adding to doubts about cholesterol lowering. Sugar-damaged lipid labels are now seen as the cause of raised ldl. Consequent under-consumption of ldl due to sugar-damage now means that statins are most probably unhelpful to most. and more research is needed in this field,  as wider segments of the population are unwisely exposed to aggressive  cholesterol lowering. It has recently been shown that high LDL cholesterol (when undamaged by sugar) is not a major cause of death at the population level [84]. Changing our current practice pattern could take many years, but we  may one day prescribe cholesterol-raising medications to certain patients [85]. The haemoglobin sugar-damage (measured as HbA1c) may prove to be surrogate indicator of for the degree of damage to LDL.

Annecdotal evidence linking HbA1c improvements to healthier lipid profiles abounds in diabetic clinics.

Re f e r e n c e s
1. Greenfeder S. Emerging strategies and agents to lower
cardiovascular risk by increasing high density lipoprotein
cholesterol levels. Curr Med Chem 2009; 16: 144-56.
2. Endo A. The discovery and development of HMG-CoA
reductase inhibitors. 1992. Atheroscler Suppl 2004; 5: 67-80.
3. Mascitelli L, Pezzetta F, Goldstein MR. Are statin effects
mediated through, or in spite of, their cholesterol-lowering
action? Angiology 2009; 60: 262-3

4. Ikonen E. Cellular cholesterol trafficking and compartmentalization.
Nat Rev Mol Cell Biol 2008; 9: 125-38.
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
muscle and liver toxicity. Atherosclerosis 2007; 195: 7-16.
7. Ravnskov U, McCully KS. Review and hypothesis:
vulnerable plaque formation from obstruction of vasa
vasorum by homocysteinylated and oxidized lipoprotein
aggregates complexed with microbial remnants and ldl
autoantibodies. Ann Clin Lab Sci 2009; 39: 3-16.

83. Howard-Alpe G, Foëx P, Biccard B. Cardiovascular
protection by anti-inflammatory statin therapy. Best Pract
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84. Danaei G, Ding EL, Mozaffarian D, et al. The preventable
causes of death in the United States: comparative risk
assessment of dietary, lifestyle, and metabolic risk factors.
PLoS Med 2009; 6: e1000058.
85. Kovesdy CP, Kalantar-Zadeh K. Lipids in aging and chronic
illness: impact on survival. Arch Med Sci 2007; 3, 4A: S74-

Cholesterol and behaviours
The neurological effects of cholesterol depletion can produce a wide range of mental conditions reported to be associated with serum cholesterol depletion. Depression, violent behaviour, homicidal behaviour and suicide are all known associates of cholesterol depletion [58, 59]. In a recent study, cholesterol content was measured in cortical and subcortical tissue of brains from 41 male suicide completers and 21 male controls. Violent suicides were found to have lower gray matter cholesterol content overall compared with nonviolent suicides and controls [60]. Randomised trials with statins have not shown a definite association between cholesterol-lowering treatment and non-illness mortality from suicides, accidents, and violence [61, 62]. However, statin trials are specifically designed to test drug efficacy, often with run-in phases, and investigators usually conduct the studies in groups of patients who have few comorbidities and are not using many concomitant medications, and when side effects are measured, their seriousness and severity are not graded. Indeed, in clinical practice it has been suggested that severe anger and irritability may occour in some statin users [63]. Neural systems have significant vulnerability to cholesterol depletion. First is the reduction in the synaptic exocytosis and endocytosis of essential signalling lipoproteins; then comes the vulnerability due to the high dependency of myelination on denovo cholesterol biosynthesis.

58. Lester D. Serum cholesterol levels and suicide: a metaanalysis. Suicide Life Threat Behav 2002; 32: 333-46.
59. Edgar PF, Hooper AJ, Poa NR, Burnett JR. Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation. Mol Psychiatry 2007; 12: 258-63. 60. Lalovic A, Levy E, Luheshi G, et al. Cholesterol content in brains of suicide completers. Int J Neuropsychopharmacol 2007; 10: 159-66.
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62. Baigent C, Keech A, Kearney PM, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90,056 participants in 14 randomised trials of statins.
Lancet 2005; 366: 1267-78.
63. Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol-lowering drugs. QJM 2004; 97: 229-35

Cholesterol-rich membrane rafts

The role of cholesterol in cellular function
became evident with the advent of the lipid raft
hypothesis [15]. The original lipid raft hypothesis
proposed the existence of assemblies of specific
lipids, that compartimentalise the plasma
membrane into functionally distinct areas [15, 16]
involved in protein sorting events in polarized cells.
It has now been clarified that lipid rafts are
cholesterol- and sphingolipid-enriched membrane
microdomains that function as platforms that
concentrate and segregate proteins within the
plane of the bilayer [17]; they are now thought to
regulate membrane trafficking in both the
exocytotic and endocytotic pathways, cell migration,
and a variety of cell signalling cascades [18].
Lipid rafts consist of both protein and lipid
components existing in continuity with non-raft
regions of membrane. Lipid-lipid interactions seem
to be of fundamental importance to the formation
of lipid rafts, with cholesterol playing a special role
as the ‘glue’ that holds these domains together [19].
The physical consequence of cholesterol
depletion in membranes is dramatically illustrated
by the experimental modelling work of de Meyer
et al. [20]. They were able to demonstrate the
manner in which cholesterol is uniquely able to
influence the structure, thickness, permeability,
deformation and other behaviours of membranes.
A state of ordered stability is attained in cholesterolrich
lipid rafts when the level reaches 20-30%
molecular cholesterol.
On the other hand, disorder, weakness and
permeability might be created in cholesterol
depleted membranes areas: cholesterol depletion
inhibiting regulated exocytosis is a key discussion
point in the review by Salaün et al. [21]. Molecule
for molecule, cholesterol can make up nearly half
of the cell membrane in lipid raft areas, cholesterol
typically makes up 20% of total lipid molecules in
the membrane [22]. Just for example, a relatively
small depletion (< 10%) in synaptosomal membrane
cholesterol has been shown to be enough to inhibit
the release of a neurotransmitter [23].

15. Simons K, Ikonen E. Functional rafts in cell membranes.
Nature 1997; 387: 569-72.
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membranes. Annu Rev Cell Dev Biol 1998; 14: 111-36.
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Symposium on Lipid Rafts and Cell Function. J Lipid Res
2006; 47: 1597-8.
18. Simons K, Toomre D. Lipid rafts and signal transduction.
Nat Rev Mol Cell Biol 2000; 1: 31-9. [Erratum in: Nat Rev
Mol Cell Biol 2001; 2: 216].
19. Barenholz Y. Cholesterol and other membrane active
sterols: from membrane evolution to “rafts”. Prog Lipid
Res 2002; 41: 1-5.
20. de Meyer F, Smit B. Effect of cholesterol on the structure
of a phospholipid bilayer. Proc Natl Acad Sci U S A 2009;
106: 3654-8.
21. Salaün C, James DJ, Chamberlain LH. Lipid rafts and the
regulation of exocytosis. Traffic 2004; 5: 255-64.
22. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P.
Molecular biology of the cell. Garland Science, 2002.
23. Waseem TV, Kolos VA, Lapatsina LP, Fedorovich SV.
Influence of cholesterol depletion in plasma membrane
of rat brain synaptosomes on calcium-dependent and
calcium-independent exocytosis. Neurosci Lett 2006; 405:

Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes?
Glyn Wainwright1, Luca Mascitelli2, Mark R. Goldstein
Cholesterol in myelination and multiple sclerosis The process in which axons are protected by the myelin secretions of the oligodendrocyte requires a specialised cholesterol-rich membrane [42]. Klopfleischet al.[43] describe experimental in vivo evidence that new myelin (re-myelination) secretion by oligodendrocytes is impaired by statins. Whilst they attribute much of this failure to signalling interference, they also prevented detrimental outcomes in vitro by re-incubating oligodendrocytes with cholesterol. How long are oligodendrocytes able to repair and maintain myelin in an environment where cholesterol is depleted? It has been argued that statins can prevent demyelination [44] through a pleiotropic anti inflammatory effect and this has led to research on its use as a multiple sclerosis therapy. This would appear to contradict Klopfleisch’s findings [43], until you consider that initially there may be multiple conflicting effects over different time scales: Possibly the initial inhibiting of an autoimmune action associated with a de-myelination and subsequent inhibition of oligodendrocyte repairs by cholesterol depletion. Research is needed to establish whether the apparent initial slowing of de-myelination in statin therapy would be followed by a catastrophic failure of the re-myelination work of oligodendrocyte exocytosis [45] as cholesterol synthesis fails. Furthermore, consideration should be given to the structural state of membranes involved in any autoimmune process where a complex interplay of essential membrane lipids, mediated by cholesterol, affects the immune response [46]

42. Fitzner D, Schneider A, Kippert A, et al. Myelin basic protein-dependent plasma membrane reorganization in the formation of myelin. EMBO J 2006; 25: 5037-48.
43. Klopfleisch S, Merkler D, Schmitz M, et al. Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo. J Neurosci 2008; 28: 13609-14.
44. Paintlia AS, Paintlia MK, Singh AK, Singh I. Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis. Mol Pharmacol 2008; 73: 1381-93.
45. Trajkovic K, Dhaunchak AS, Goncalves JT, et al. Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J Cell Biol 2006; 172: 937-48.
46. Harbige LS. Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 2003; 38: 323-41

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