Sunday, 28 May 2017

Damaging Cholesterol

I recently asked how can statins work in secondary progressive MS.


In the absense of any real insight, I came up with a few ideas one of which was involving the cholesterol pathway to control/induce nerve damage

Bezine M, Debbabi M, Nury T, Ben-Khalifa R, Samadi M, Cherkaoui-Malki M, Vejux A, Raas Q, de S├Ęze J, Moreau T, El-Ayeb M, Lizard G. Evidence of K+ homeostasis disruption in cellular dysfunction triggered by 7-ketocholesterol, 24S-hydroxycholesterol, and tetracosanoic acid (C24:0) in 158N murine oligodendrocytes. Chem Phys Lipids. 2017 pii: S0009-3084(17)30011-7

Imbalance in the homeostasis of K+ ions has been reported to contribute to the pathogenesis of neurodegenerative diseases. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC), and tetracosanoic acid (C24:0), often found at increased levels in patients with Alzheimer's disease and Multiple Sclerosis, are able to trigger numerous nerve cell dysfunctions.  We therefore studied the impact of 7KC, 24S-OHC, and C24:0 on 158N mouse oligodendrocytes, and determined their impact on K+ homeostasis. The effects of 7KC, 24S-OHC and C24:0 on lipid membrane organization and membrane potential were examined. 7KC, 24S-OHC and C24:0 induced changes in lipid content and the cytoplasmic membrane. These events were associated with increased [K+]i. The positive correlation between [K+]i and cell death supports the potential involvement of K+ in 7KC-, 24S-OHC-, and C24:0-induced cytotoxicity.
Cholesterol can be oxidised to become agents called oxysterols (see the diagram above). These can bind to cells including oligodendrocytes and they can block the action of a number of ion channels including some potasium channels and also potassium and sodium exhangers. These cause a rise in the concentration of potassium within the cell, which eventually trigger the entry of calcium and the suicide of the cell. This is a mechanism of inducing cell death in oligodendrocytes as shown here, but probablyother cell types as well

Statins will get rid of the cholesterol and in doing so will remove oxysterols and so this damaging mechanism will not occur. Perhaps getting rid of some of the potassium from inside the cell may be a route to countering this problem. I could suggest how this appraoch may be achieved but that's another post.

8 comments:

  1. Is it not true that statins may - by reducing cholesterol - increase cancer risk particularily in certain groups, e.g. the elderly, who may have occult cancers, early stage cancers? Because cholesterol is involved in immune system function, e.g. dealing with microbes? Reading some of the research into statins, I'm surprised that they don't actually make MS worse.

    ReplyDelete
    Replies
    1. They don't. But there is this suggestion when given interferon beta.

      Delete
  2. This is the brain own cholesterol?
    The one you said has a half life of 6 months to 5 years?
    From the may 10 post, most of the theraphies are for cholesterol in the plasma ,how this will control brain cholesterol?
    Nice post
    Luis

    ReplyDelete
  3. We don't yet really understand statin's efficacy in cardio indications:

    http://blogs.sciencemag.org/pipeline/archives/2016/12/14/simple-right

    ReplyDelete
  4. We suggested that it may take time for statins to act
    https://www.ncbi.nlm.nih.gov/pubmed/27180285

    ReplyDelete
  5. Have you ever commented on this article? https://www.ncbi.nlm.nih.gov/pubmed/22384749

    ReplyDelete
    Replies
    1. before my time on the blog and we often do not report on review hypothesis papers.

      Delete
  6. And it seems that EBV alters cholesterol, and it needs cholesterol for its viral latency.


    https://www.ncbi.nlm.nih.gov/pubmed/20594556

    https://www.ncbi.nlm.nih.gov/pubmed/17150237

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.