NZer1 wrote:THE LIPID HYPOTHESIS
Corthals believes that the primary cause of MS can be traced to transcription factors in cell nuclei that control the uptake, breakdown, and release of lipids (fats and similar compounds) throughout the body. Disruption of these proteins, known as peroxisome proliferator-activated receptors (PPARs), causes a toxic byproduct of "bad" cholesterol called oxidized LDL to form plaques on the affected tissue. The accumulation of plaque in turn triggers an immune response, which ultimately leads to scarring. This is essentially the same mechanism involved in atherosclerosis, in which PPAR failure causes plaque accumulation, immune response, and scarring in coronary arteries.
This is an interesting idea. There are some reports of an association of lipid markers with multiple sclerosis activity. For instnace:
In one report on patients on beta-interferons...
1) Higher LDL is associated with new T2 lesions
2) Higher free thyroxine is associated with enhancing lesions
3) Higher HDL is associated with deseasonalised 1,25-dihydroxy vitamin D3
There has been some association of t-cell function with lipid "rafts". For instance, one investigator reports and 7-keto cholesterol reduces the "lipid order" of the cell membrance and reduces t-cell activation.
Source: http://www.futuremedicine.com/doi/full/ ... /imt.13.19
A cross sectional study suggests a difference in [peripheral] mononuclear cell membrane composition and EDSS functional system scores (sensory and cerebral scores)
In MS patients, oxidized-LDL correlated with higher EDSS
In another cross sectional study, high LDL, higher total cholesterol, and higher triglycerides were associated with higher EDSS (HDL with no effect on EDSS). T2 lesion volume was not associated with these variables. The authors speculate that there may be a link between the vascular endotheleum of the blood brain barrier and multiple sclerosis, possibly through extravasation of immune cells. They also feel that cerebral hypoperfusion may contribute.
Of course, Dr. Swank found a benefit of a low saturated fat diet in MS [nonrandomized/unblinded trial; possible recall bias]
Smoking [a known cardiovascular risk factor] is also associated with worse prognosis in MS.
"In the context of autoimmunity, the various risk factors for MS are frustratingly incoherent," Corthals said. "But in the context of lipid metabolism, they make perfect sense."
This goes to far I think. I wouldn't say that the autoimmune risk factors are "incoherent." It's just that no single risk factor has great significance. The same, I would argue, is true with markers of lipid metabolism. I don't think it's really fair to asay that the association of lipid metabolism of MS "make[s] perfect sense."
The problem is that a lot of the cardiovascular risk factors are not related to multiple sclerosis, so it seems silly to create an analogy to atherosclerosis.
For instance, advanced age and male sex are not linked to MS.
Hypertension is not linked to MS
coronary artery disease to our knowledge is not strongly linked to MS.
There is evidence to suggest that there is no association of premorbid lipid intake and development of multiple sclerosis.
For instance, the massive Harvard nursing study (undoubtedly a higher quality study than any listed above) revealed no significant effect, except possibly for linolenic acid (nonsignificant)
The benefit of statins is also questionable, as studies have had mixed results. Check out the following if you have time:
The most famous of the trials is the STAYCIS trial at UCSF (statins to prevent conversion of CIS to MS) which failed to meet its primary endpoint
Source: Waubant E, Pelletier D, Mass M, Cohen J, Kita M, Cross A, Bar-Or A, Vollmer T, Racke MK, Stüve O, Atorvastatin therapy in patients with Clinically Isolated Syndrome (CIS): the STAyCIS study. 134th Annual Meeting, American Neurological Assocation; Baltimore, MD. 2010.
The SIMCOMBIN trial (statins in MS patients on beta interferons) was also negative.
I wish that we could get some very high quality preclinical evidence about what lipid profile changes are associated with multiple sclerosis to plan interventions. I think that this is very promising.
If someone is aware of such data, please let me know.