How do statins Work?..or Do they?

H

A few days ago we did a piece about how do statins work. I think we came up with a list of a few options but I admit some were missing as pointed out by one of our regular commenters. I thought about doing a piece as it is a bit awkward to do trials (e.g. MS-STAT) and not have a reasonable idea how the treatments may work as I did not buy the ideas being suggested.

In the post. I mentioned Oxysterols. Oxysterol is a derivative of cholesterol obtained by oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasislipid metabolismapoptosisautophagy, and prenylation of protein/. I was thinking that they could be involved in protecting oligodendrocytes and microglia. This occurred after I read some work by:

Bezine M, Maatoug S, Ben Khalifa R, Debbabi M, Zarrouk A, Wang Y, Griffiths WJ, Nury T, Samadi M, Vejux A, de Sèze J, Moreau T, Kharrat R, El Ayeb M, Lizard G. Modulation of Kv3.1b potassium channel level and intracellular potassium concentration in 158N murine oligodendrocytes and BV-2 murine microglial cells treated with 7-ketocholesterol, 24S-hydroxycholesterol or tetracosanoic acid (C24:0). Biochimie. 2018 Oct;153:56-69. doi: 10.1016/j.biochi.2018.02.008. 

I even tried to set a collaboration with Drs Bezine and Lizard and we wrote a few grants together, but without support from France or the UK, there was not enough to get the group to focus on multiple sclerosis and Dr Benzine finished her PhD and went off into the research sunset. Maybe it was a rubbish idea. The idea was that the oxysterols were actiing on potassium channels but this study argues something else

6.35 Cholesterol Synthesis | Nutrition Flexbook
Statins block HMG Co-A = HMGCR to block cholesterol with is downstream from Squalene

So perhaps we should not act why they work but why they dont work as the statin would block squalene production.

The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.

Brain Seq data

Therefore based on this idea statins would inhibit repair. This has been suggested before… Statin Therapy Inhibits Remyelination in the Central Nervous System.

As is the case of many things the actual efffect is the balance of good and unwanted things. So if MS-SMART doesn’t work you can say repair was an issue, but if it does work then maybe this pathway is not that important.

The data is what the dat will be, in hindsight on can say i told you so and if the vision is wrong you can blasts the animal data.

Relevance to multiple sclerosis. The data are relevant for human MS, which showed downregulation of DHCR24 expression and upregulation of LXR target gene expression in repairing lesion areas. It is tempting to presume that persistent MS lesions are the sites where local repair mechanisms involving active sterol IFNβ-1b DMHCA Desmosterol mimetic Squalene Desmosterol Anti-inflammatory LXR activation . (Sadly a chink in the argument is must beta interferon going to get in the CNS I doubt it)

We speculate that the local coincidence of extensive demyelination (cholesterol uptake blocking sterol synthesis), auto-aggressive immune cells (activating microglia/macrophages) and ‘above-threshold’ microglial perturbation with the combined effects of aging (lipofuscin deposits, cholesterol crystals and epigenetic changes) causes lesion pathology. In contrast, normal-appearing white matter would not exceed this ‘threshold’ of microglia/macrophage impairment. Here, inflammation would largely resolve and lesions would quickly remyelinate, possibly even without leaving visible pathology, as suggested by gene expression profiles and carbon-14 dating.

Therapeutic implications. In MS, there is an urgent need for therapeutic strategies targeting both inflammation and remyelination4 . To show proof of principle for the critical role of desmosterol in microglia, we have successfully applied the desmosterol mimetic DMHCA (a synthetic LXR agonist), which efficiently targets traumatic brain injury in mice. In models of inflammatory demyelination, the combination of this synthetic LXR agonist with a first-line anti-inflammatory MS medication and squalene achieved the greatest therapeutic benefits. The natural compound squalene feeds into sterol synthesis and enhances the synthesis of desmosterol in microglia/macrophages (anti-inflammatory mode of action) and cholesterol synthesis in oligodendrocytes for myelination (remyelinating mode of action). Importantly, squalene administration was well tolerated in mice, in agreement with studies in humans. Interestingly, Mediterranean diets may reduce disease severity in MS. The Mediterranean lifestyle can result in squalene consumption levels of 200–400mg per day (compared to 30 mg per day in the United States). Thus, squalene supplementation should be further investigated as a therapeutic strategy in human MS.

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MouseDoctor

1 comment

  • https://www.youtube.com/watch?v=ZelPcA2Dz2c

    Shaw that study eyestarday and thought that was important and somehow related to statins cholesterol pathway

    So they say the vacuum cleaner cells (microglia .macrophages) are damage they “suffocate” from to much myelin

    And in the process not able to recycle the cholesterol needed to make myeling sheats again

    They became foam cells

    In the end if they deliver pharmacological deliver squalene the myelin repair can happen again

    So my question is why those vacuum cleaner cell became fill with to much myelin in the first place?

    And if that is the case could pwms with bigger demyelinatio/ lesions could exacerbate that process ?

    Obrigado

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