Pleiotropic effects of statins via interaction with the lipid bilayer: A combined approach

Penkauskas, Tadas; Zentelytė, Aistė; Ganpule, Shamish; Valinčius, Gintaras; Preta, Giulio

doi:10.1016/j.bbamem.2020.183306

Cited by 23 publications

(24 citation statements)

References 90 publications

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“…Evidence suggests that a relationship exists between statin lipophilicity and pleiotropy, which supports the hypothesis that the effects of statins are dependent on where it resides within biological membranes [28][29][30]. It is known that the inclusion of amphiphiles into lipid bilayers impacts lipid bilayer parameters like permeability and thickness [104,105].…”

Section: Statin-membrane Interactionssupporting

confidence: 54%

“…The inconsistency in these rates has many potential explanations, including broad definitions of myopathy, exclusion of groups (i.e., previously statin-intolerant patients), and the nocebo effect [ 26 , 27 ]. The cause of statin-induced myopathy remains unknown, yet there is an expanding body of evidence for the relationship between lipophilicity and pleiotropy of a given statin [ 28 , 29 , 30 ]. This is based on the hypothesis that describes the biological effects of statins as being dependent on where they reside within cell membranes [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Murphy

Deplazes

Cranfield

et al. 2020

IJMS

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Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

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Section: Statin-membrane Interactionssupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Murphy

Deplazes

Cranfield

et al. 2020

IJMS

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“…Changing the membrane bilayer properties such as intrinsic curvature, elasticity and fluidity is a characteristic of several amphiphilic molecules. Statins, beyond the classical cholesterol lowering effects have been shown to alter lipid organization of artificial membranes and cell membranes in a cholesterol-independent way ( Redondo-Morata et al, 2016 ; Penkauskas et al, 2020 ). This property can be included among the pleiotropic effects of statins, which are behind many benefits observed during statin therapy ( Banfi et al, 2017 ; Oesterle et al, 2017 ).…”

Section: Amphiphilic Molecules In Cancer Therapymentioning

confidence: 99%

“…According to an established hypothesis, the biological properties of statins depend on their localization in the cellular membrane due to their amphiphilic properties ( Mason et al, 2005 ; Galiullina et al, 2017 ). Several recent studies investigated the interactions of different statins with phospholipid membranes and their influence on the membrane structure ( Sahu et al, 2019 ; Sariisik et al, 2019 ; Penkauskas et al, 2020 ). Statins seem to bind and influence lipid membranes, possessing different average location into the bilayer ( Galiullina et al, 2019 ).…”

Section: Amphiphilic Molecules In Cancer Therapymentioning

confidence: 99%

“…The dynamin inhibitor Dynasore has been shown to influence both cholesterol transport on the cell membrane and cholesterol concentration ( Girard et al, 2011 ; Preta et al, 2015a , b ). Beyond the cholesterol-lowering effects of statins, cholesterol-independent or pleiotropic effects are reported, including the capacity to modify plasma-membrane organization and structure ( Wang et al, 2008 ; Penkauskas et al, 2020 ). Studies using artificial model membranes showed that statins alter the nanomechanical stability of the bilayers, intercalating the lipid-water interface and increasing membrane heterogeneity ( Redondo-Morata et al, 2016 ; Galiullina et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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New Insights Into Targeting Membrane Lipids for Cancer Therapy

Preta

2020

Front. Cell Dev. Biol.

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Modulation of membrane lipid composition and organization is currently developing as an effective therapeutic strategy against a wide range of diseases, including cancer. This field, known as membrane-lipid therapy, has risen from new discoveries on the complex organization of lipids and between lipids and proteins in the plasma membranes. Membrane microdomains present in the membrane of all eukaryotic cells, known as lipid rafts, have been recognized as an important concentrating platform for protein receptors involved in the regulation of intracellular signaling, apoptosis, redox balance and immune response. The difference in lipid composition between the cellular membranes of healthy cells and tumor cells allows for the development of novel therapies based on targeting membrane lipids in cancer cells to increase sensitivity to chemotherapeutic agents and consequently defeat multidrug resistance. In the current manuscript strategies based on influencing cholesterol/sphingolipids content will be presented together with innovative ones, more focused in changing biophysical properties of the membrane bilayer without affecting the composition of its constituents.

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Statin therapy and risk of Alzheimer's and age‐related neurodegenerative diseases

Torrandell‐Haro

Branigan

Vitali

et al. 2020

A&D Transl Res & Clin Interv

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Introduction Establishing efficacy of and molecular pathways for statins has the potential to impact incidence of Alzheimer's and age‐related neurodegenerative diseases (NDD). Methods This retrospective cohort study surveyed US‐based Humana claims, which includes prescription and patient records from private‐payer and Medicare insurance. Claims from 288,515 patients, aged 45 years and older, without prior history of NDD or neurological surgery, were surveyed for a diagnosis of NDD starting 1 year following statin exposure. Patients were required to be enrolled with claims data for at least 6 months prior to first statin prescription and at least 3 years thereafter. Computational system biology analysis was conducted to determine unique target engagement for each statin. Results Of the 288,515 participants included in the study, 144,214 patients (mean [standard deviation (SD)] age, 67.22 [3.8] years) exposed to statin therapies, and 144,301 patients (65.97 [3.2] years) were not treated with statins. The mean (SD) follow‐up time was 5.1 (2.3) years. Exposure to statins was associated with a lower incidence of Alzheimer's disease (1.10% vs 2.37%; relative risk [RR], 0.4643; 95% confidence interval [CI], 0.44–0.49; P < .001), dementia 3.03% vs 5.39%; RR, 0.56; 95% CI, 0.54–0.58; P < .001), multiple sclerosis (0.08% vs 0.15%; RR, 0.52; 95% CI, 0.41–0.66; P < .001), Parkinson's disease (0.48% vs 0.92%; RR, 0.53; 95% CI, 0.48–0.58; P < .001), and amyotrophic lateral sclerosis (0.02% vs 0.05%; RR, 0.46; 95% CI, 0.30–0.69; P < .001). All NDD incidence for all statins, except for fluvastatin (RR, 0.91; 95% CI, 0.65‐1.30; P = 0.71), was reduced with variances in individual risk profiles. Pathway analysis indicated unique and common profiles associated with risk reduction efficacy. Discussion Benefits and risks of statins relative to neurological outcomes should be considered when prescribed for at‐risk NDD populations. Common statin activated pathways indicate overarching systems required for risk reduction whereas unique targets could advance a precision medicine approach to prevent neurodegenerative diseases.

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Pleiotropic effects of statins via interaction with the lipid bilayer: A combined approach

Cited by 23 publications

References 90 publications

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Statin therapy and risk of Alzheimer's and age‐related neurodegenerative diseases

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