Thursday, 26 January 2017

Cholesterol makes myelin...should we be eating bad fat.

Berghoff SA, Gerndt N, Winchenbach J, Stumpf SK, Hosang L, Odoardi F, Ruhwedel T, Böhler C, Barrette B, Stassart R, Liebetanz D, Dibaj P, Möbius W, Edgar JM, Saher G. Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.
Nat Commun. 2017 Jan 24;8:14241. doi: 10.1038/ncomms14241.

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes.


The message of the paper is that dietary cholesterol may be useful in myelin repair and as myelin is largely fat, is it surprising that there could be some influence on myelination. The implications are clear, but before you start diving into that plate of cheese, there needs to be some balance.
                                New MS Treatment for Repair

Whilst the inference of the mouse study is that increasing cholesterol will promote remyelination, however there is even more evidence that elevated cholesterol levels are risk factors for a large number of conditions, including cardio-vascular disease. 

To deal with this, statins have become a main agent to treat the effects of dietary cholesterol. 

The ARRIVE guidelines of reporting animal studies suggest that you discuss the work within the context of previous studies and also to discuss the implications for translation into humans. 


This manuscript is lacking, in an adequate discussion that encompasses the substantial literature surrounding the cholesterol pathway and the use of statins.  I guess to acknowledege the exsistence of such limits the novelty of the approach, so the contents of reference 43 were never discussed. 

Dietary cholesterol did not inhibit or augment EAE as shown here, but we and others have shown that blocking cholesterol does not inhibit or augment EAE. The effect of statins in EAE appears to be upstream of cholesterol and they can inhibit EAE. More importantly are the reports that statins can inhibit remyelination. Which supports the claims here and again asks what's new here?


Miron VE, Zehntner SP, Kuhlmann T, Ludwin SK, Owens T, Kennedy TE, Bedell BJ, Antel JP. Statin therapy inhibits remyelination in the central nervous system. Am J Pathol. 2009; 174:1880-90.


Although there is some confusion. 


Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I. HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J. 2005 19(11):1407-21 is right


There are obvious implications from this for the use of statins in MS. This current study would imply that statins would have a negative impact on MS.

However, there is a suggestion that simvastatin slowed the worsening associated with secondary progressive MS in a phase II trial. Therefore, on balance the data would imply the any adverse influence on remyelination is negated.


Six years after the publication of the MS-STAT phase II trial, could a phase III come to the table?.

This would raise some questions that may or may not have answers:

1. In light of this study should a neuroprotection trial be done? Do we ignore the animal data(...so what's new there?) and carry-on?.


2. Do the statin investigators have a plausible mechanism to under-pin the basis of the trial?  A trial with a rationale mechanism surely has more chance of success than a stab in the dark. Is it another look-see punt in the dark? or should I say punt in the dusk, as the phase II trial was the shot in the dark. 

The original mechanism was that statins influenced either the cytokine balance or white cell migration, which had their targets firmly in relapsing MS. Statins didn't fair sufficiently well for relapsing MS but the logic of trying statins in secondary progressive MS, was never really expanded upon or clear to me.


Given the link of Alzheimer’s, progressive EAE and the cholestrerol pathway one can construct one, but surely this is a job for the Investigators.

3. What will the trial be like?…will they go cheap and fail you by only testing the high-dose used in the phase II trial. 


A normal dose is needed to show the added risks of the high-dose are warranted. Dose response is what academics/regulators have made pharma do, so I really hope this is done. But it will add to the costs.

Would a phase III study be adequately powered, as academic trials often over-state the likely treatment effect to reduce the numbers, to detect change, to reduce costs.

4. Would they determine where the statins are working. Is it neuroprotection by affecting nerves within the brain, or are they simply affecting a co-morbidity, which could be done by comparing a CNS penetrant verses a non-CNS penetrant statin.

I suspect too much science for a trial.

5. Is it a drug-lite trial of only statin verses placebo, as the biology indicates that it would best be done on top of an anti-inflammatory, immune-modulator.

6. What is the plan post trial?.  Is the hope, that if positive, neuros will just use it. But will they? Will pharma be annoyed that they have to do two properly powered trials and spend millions getting drugs approved. If one ploughs on and people don't adopt it will be 5 years wasted, or is the PR of doing a trial more important that success.


Importantly, what happens once pharma gets something approved eg ocrelizumab or siponimod, which may happen before the trial is finished. What will neuros do.

Maybe, I have it all wrong and the rumors are just rumors 

9 comments:

  1. Fat is good, but it has to be mostly omega 3 fat from fish, plants or oils. Saturated fat promotes inflamation.

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    1. The hard evidence to support this about omega 3 is weak and often speculative at best..Indeed read another attempt in a paper this morning.

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    2. If you find a paper worth posting would be interested to read your take on it MD. Don't waste your time though, not eating too much cheese (sigh) is good for me anyway ;-)

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  2. Funny reading this reminded me of my Austria grandmother who lived until the ripe old age of 96. She always used to tell me to eat the fat on meat. She claimed the nerves needed it, she said they needed the fat to "coat" them. These old wives tales really do contain some truths.

    My mother as a child in the 50s was given daily large spoonfuls of cod liver oil amongst other strange concoctions. I wish it had carried on. It could have helped me avoid developing ms as I now look back and see there were warning signs. I believe I've always been vitamin d deficient. As a child I had brown marks on my milk teeth. I also l, as a child aged approx 6, tried to get up out of bed one day and had no power in my legs. I collapsed and could not walk. The GP told my weeping mother that it was just a virus. The power did return to my legs but I've always wondered what caused this. Any ideas doctors?

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    1. When I was 6, one of my arms suddenly stopped working. From what I remember, the GP/Pediatrician had no proper explanation. My then 3-year old brother had pulled/twisted my arm a few days earlier, and I decided that was the cause. The arm went back to normal after some days.
      (My elderly parents dont remember any of this now)

      Many years later, one of my children (now an adult) was diagnosed with MS at age 12. Another has had various symptoms but a clear MRI and no diagnosis.

      Dealing with all this made me something of an MS expert. Then a few years ago, I myself developed some mild tingling, numbness, weakness, etc - and it turned out my brain and spine have many old lesions. Repeated the MRI after a year, and a few more had appeared.


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  3. Not at all sure what the first paper was about? We get very little cholesterol from our diet in any case. We make it, mainly for use in bile (and other useful stuff) so we can absorb all the fat we eat.

    Primary care drug budgets went through the roof in the 90s thanks in part to statins (not to mention SSRIs, H2 ants and PPIs) all off patent now :-) Pharma will love the chance for a second bite at the statin cherry ;-)

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  4. Remember there are two types: LDL (Bad) Cholesterol and HDL (Good) Cholesterol. Which of the two makes myelin?

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  5. I love cheeses, but I'm careful because I also take vitamin D3.

    This publication reminds me of another one I made now that potato chips are good if it is fried in extra virgin olive oil, and if the potato is fresh.

    http://www.ugr.university/pages/ugr_news/news_archive/science/benefitsofevoo

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  6. This comment has been removed by the author.

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