Is cholesterol truly bad for you?

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Low-density lipoprotein particle, apolipoprotein B (blue) is surrounded by various forms of cholesterol (orange and yellow) and other lipids.
JUAN GAERTNER/SCIENCE PHOTO LIBRARY

Scientists have known for a long time that cholesterol like other basic food components forms an essential component in a healthy human body. It forms the cell membrane architecture (or the cell wall), helps produce the sex hormones, and assists in the formation of bile that helps in the digestion of food. The dietary guidelines recommend an intake of 200-300mg of cholesterol daily. It is important to understand that your own body produces cholesterol in the liver, in addition to what is consumed in your diet. Plants, on the other hand cannot produce cholesterol, and therefore dietary sources of cholesterol remain meat and diary.

Cholesterol is carried around the bloodstream attached to low-density lipoprotein (LDL) “bad cholesterol” and high-density lipoprotein (HDL) “good cholesterol”. Your doctor has probably requested this on a number of occasions as a blood test to evaluate your cardiovascular risk. Recently, another biomarker Apolipoprotein B (ApoB) has come to the forefront as being a better representation of the number of cholesterol-laden particles circulating in the blood stream.

In MS higher total cholesterol and LDL-cholesterol levels have been linked to worsening disability, with greater ApoB levels at disease onset being linked to increased number of lesions on MRI brain scans over a 2 year period. Whether, there may be link with the underlying neurodegeneration is unknown, and forms the focus of the study presented below.

Murali et al. in Buffalo, New York, studied the longitudinal changes of cholesterol biomarkers (total cholesterol, HDL-C, LDL-C, Apo profiles and their genotyping) over a 5 year period in healthy subjects and MS, and their relationship with brain lesions and volume loss. The study involved 41 healthy controls (HC), 76 relapsing-remitting MS (RR-MS), and 37 progressive MS (P-MS) subjects.

They found that, whilst a rise in LDL-C was associated with the development of new MS lesions, HDL-C and ApoA-I (a component of HDL-C) were associated with less grey matter and cortical volume loss (area of the brain where the neuronal cell bodies sit). The highest quartiles of LDL-C were linked to the greatest number of new MS lesions (see Figure 1 below). The opposite was true for HDL-C with the lowest quartile of HDL-C change being associated with more gray matter and cortical volume loss. Both imply, that extremes in change are somehow very harmful; that is to to high LDL-C levels or to low HDL-C levels.

Figure 1: A is bar graph of the number of new T2 lesions at 5-year follow-up versus the quartiles of low-density lipoprotein cholesterol (LDL-C) percent change and B the quartiles of total cholesterol (TC) percent change. 1C, and Figure 1E are bar graphs representing the mean percent annual changes innormalized gray matter volume at 5-year follow-up against the quartiles of high-density lipoprotein cholesterol (HDL-C) percent change and quartiles of apolipoprotein A-I (ApoA-I) percent change. 1D and Figure 1F are bar graphs representing the mean percent annual changes innormalized neocortical gray matter volume (y-axis) at 5-year follow-up against the quartiles of high-density lipoprotein cholesterol (HDL-C) and quartiles of apolipoprotein A-I (ApoA-I) percent change.

Moreover they observed something interesting in the who did and did not progress (of the 76 RRMS, 11 converted to SPMS; these numbers are small and any interpretation of the findings should be noted with caution). Although, the converted and non-converted did not differ by total cholesterol levels, the percentage rise in HDL-C was much greater in the non-converted group (data not shown here). However, there were no differences noted in the percentage ApoB change.

The important question then becomes, how much weight should we place on good versus bad cholestrol in our body compositions? And, one also wanders whether these findings are bystander changes, more reflective of the association between cholesterol and inflammation, rather than a direct effect of cholesterol levels on disease activity and progression.

Abstract

Cholesterol and Neurodegeneration: Longitudinal Changes in Serum Cholesterol Biomarkers Are Associated with New Lesions and Gray Matter Atrophy in Multiple Sclerosis Over 5-years Follow-up.

Murali N, Browne RW, Fellows Maxwell K, Bodziak ML, Jakimovski D, Hagemeier J, Bergsland N, Weinstock-Guttman B, Zivadinov R, Ramanathan M.

BACKGROUND:

Cholesterol is an important structural component of myelin and essential for brain homeostasis.

OBJECTIVE:

To investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS).

METHODS:

This prospective, longitudinal study (n = 154) included 41 healthy controls (HC), 76 relapsing-remitting MS (RR-MS), and 37 progressive MS (P-MS) subjects. Neurological examination, brain MRI and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and the apolipoproteins (Apo), ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped.

RESULTS:

Greater percent increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percent increases in LDL-C were associated with increases in new T2 lesions. The percent increases in HDL-C (p = 0.032) and ApoA-I (p = 0.007) were smaller in the patients RR-MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status.

CONCLUSIONS:

Increases in HDL-C and ApoA-I have protective associations with MRI measures of neurodegeneration in MS. This article is protected by copyright. All rights reserved.

About the author

Neuro Doc Gnanapavan

15 comments

  • Cholesterol play a role in cell migration and prroliferation

    Considering that T cell activation generally triggers a large-scale proliferation of the activated cells, anabolic pathways are critical during this process of activation. This has been well established in cancer cells, where high proliferation is the primary defining characteristic (15, 16). Treating a population of naïve T cells with Statin suppresses progression of their differentiation and cell cycle. Statin is an inhibitor of HMG-CoA reductase, the enzyme responsible for catalysis in the rate-limiting step of cholesterol biosynthesis. Furthermore, inhibition of this enzyme leads to decreased rates of DNA synthesis in many highly proliferative cell populations, such as lymphocytes, fibroblasts, and PDGF-treated smooth-muscle cells (17, 18). These downstream effects of statin treatment play a role in stagnating T cell activation. It is important to note, that not all statin-mediated changes in the cell are inherently tied to cholesterol levels. As statins inhibitory target is further upstream from cholesterol synthesis, cholesterol-independent effects may be at work as well.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711771/

      • All I know is that when I was put on statins my LDL levels halved and HDL went up – I think this is normal. MS diagnosis came later, My MS is ‘not active’. No idea whether there is any connection (sample size 1!) but I’m happy to stay on statins (lipitor in my case) as a safe insurance policy and know plenty of others who do the same.

      • Phase II study in SPMS found in a select group of patients that high dose statin slowed down the rate brain volume loss. They’re currently recruiting for a phase II study (MS- STAT2).

      • ……This
        suggests that simvastatin’s beneficial effects in MS are independent
        of its effect on lowering peripheral cholesterol levels, implicating
        a role for upstream intermediate metabolites of the
        cholesterol synthesis pathway. Importantly, it demonstrates that
        computational models can elucidate the causal architecture underlying
        treatment effects in clinical trials of progressive MS.

        Applying causal models to explore the mechanism of
        action of simvastatin in progressive multiple sclerosis

        https://www.pnas.org/content/116/22/11020

  • Background: Current treatments for relapsing remitting multiple sclerosis (RRMS) reduce inflammation, but
    have a partial or modest effect on disability. This effect may require a much longer follow-up than standard trial
    design, in particular in RRMS with relatively-preserved functional reserve. We aimed to assess the long-term
    clinical evolution of RRMS patients exposed to atorvastatin in two trials (ACTIVE and ARIANNA).
    Methods: We retrospectively looked at 69 participants randomized with atorvastatin or placebo as add-on
    therapy to interferon-beta for 24 months at a single MS centre. We recorded relapses, 1-point EDSS progression
    and progression to EDSS 4.0. Cox regression was performed for these three questions. A Poisson regression model
    was used to evaluate the association between atorvastatin treatment and annualized relapse rate (ARR).
    Results: After 8.4 ± 2.3 (3.7–11.9) years from trial, the use of atorvastatin was associated with reduced risk of
    1-point EDSS progression (HR=0.440; 95%CI=0.225–0.861; p=0.017), and of EDSS 4.0 (HR=0.310;
    95%CI=0.123–0.784; p=0.013). We found no significant association between atorvastatin and relapses.
    Discussion: These data suggest that a delayed treatment effect may be seen with atorvastatin added to interferonbeta,
    eight years after entering the clinical trials. Long-term follow-up of trial cohorts should be mandated.

    Therapeutic lag in reducing disability progression in relapsing-remitting
    multiple sclerosis: 8-year follow-up of two randomized add-on trials with
    atorvastatin

    Multiple Sclerosis and Related Disorders 28 (2019) 193–196

  • So should we all be on statins then?
    And would the text above tie into what OMS seems to be about with regards to bad cholesterol etc?

    • The data is promising, but doses used are quite variable and not everyone benefits. Without a large phase III study all of this Phase II data only goes so far. And you cannot make treatment recommendations on it. Statins have side effects worse being an inflammatory myositis (inflammation of the muscles) and you can loose muscle mass very quickly from this!

  • I have been trying to reach the magic 80 mg dose of simvastatin but become hugely constipated on 50
    Is taking some better than taking none?
    will all statins have the same benefit on MS as simvastatin and if so do some cause fewer instances of constipation for example?

    • The answer to that one is that we don’t know, the MS-STAT1 study only used 80mg/day and drug levels were not analysed – so no idea on the effective dose…

      • Thank you for your reply
        Do you know why they chose such a high dose then?
        And will all statins be as effective?
        I assume they used simvastatin because of cost

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