Eicosapentaenoic acid membrane incorporation impairs ABCA1-dependent cholesterol efflux via a protein kinase A signaling pathway in primary human macrophages

Fournier, Natalie; Tardivel, Sylviane; Benoist, Jean‐François; Védie, Benoît; Rousseau-Ralliard, Delphine; Nowak, Maxime; Allaoui, Fatima; Paul, Jean–Louis

doi:10.1016/j.bbalip.2016.01.002

Cited by 20 publications

(12 citation statements)

References 68 publications

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“…High cholesterol levels prevent SREBP2 activation, inhibiting the subsequent induction of HMGCR and maturation of LDLR (Figure 4J) 19 . Studies in human macrophages have observed that incorporation of EPA into the plasma membrane impairs ABCA1-dependent cholesterol efflux 38, 39 , but our study is the first to report this phenomenon in cancer xenograft models. Here, we demonstrated that suppression of ABCA1 activity by the combination of EPA with EPHA2 inhibition induced the accumulation of cellular cholesterol, contributing to increased membrane polarity, inhibition of SREBP2, disruption of cellular lipid homeostasis, and apoptosis (Figure 4K).…”

Section: Discussionmentioning

confidence: 57%

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Torres-Adorno

Vitrac

et al. 2018

Oncogene

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Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell-surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2 specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and pre-clinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC.

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Section: Discussionmentioning

confidence: 57%

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Torres-Adorno

Vitrac

et al. 2018

Oncogene

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“…The third limitation is that the status of endogenous cholesterol donors would not be accounted for in in vitro CEC assays. Changes of in vivo macrophage cellular function resulting from various conditions have been reported as follows: phenolic acids increased ABCG1 and SR-BI expression 66) ; on the other hand, xanthine oxidoreductase suppressed ABCA1 and ABCG1 expression in macrophages 67) ; while we have demonstrated that EPA could improve CEC 45, 46) , another group has reported that EPA might reduce ABCA1 functionality in macrophages 68) .…”

Section: Limitations Of Conventional Cec Assaysmentioning

confidence: 67%

Assessment of HDL Cholesterol Removal Capacity: Toward Clinical Application

Toh

2019

J Atheroscler Thromb

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While there is a controversy regarding the causal relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD), recent studies have demonstrated that the cholesterol efflux capacity (CEC) of HDL is associated with the incidence of CVD. However, there are several limitations to current assays of CEC. First, CEC measurements are not instantly applicable in clinical settings, because CEC assay methods require radiolabeled cholesterol and cultured cells, and these procedures are time consuming. Second, techniques to measure CEC are not standardized. Third, the condition of endogenous cholesterol donors would not be accounted for in the CEC assays. Recently, we established a simple, high-throughput, cell-free assay system to evaluate the capacity of HDL to accept additional cholesterol, which is herein referred to as “cholesterol uptake capacity (CUC)”. We demonstrated that CUC represents a residual cardiovascular risk in patients with optimal low-density lipoprotein cholesterol control independently of traditional risk factors, including HDL-C. Establishing reproducible approaches for the cholesterol removal capacity of HDL is required to validate the impact of dysfunctional HDL on cardiovascular risk stratification in the “real world”.

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“…n -3 PUFAs appear to have diverging effects on macrophage-specific cholesterol efflux in mice and in humans. In vitro studies showed that EPA impairs ABCA1 mediated cholesterol efflux in both human and murine macrophages, whereas DHA stimulates ABCA1 dependent efflux in murine macrophages [ 46 ]. Chadli et al as well as Nishimoto et al reported n -3 PUFAs ( n -3 PUFA oil mixture; EPA) to stimulate RCT, which was reflected by increased fecal sterol excretion [ 27 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Omega-3 Fatty Acids in Reverse Cholesterol Transport: A Review

et al. 2017

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The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular disease have been studied extensively. However, it remains unclear to what extent n-3 PUFAs may impact Reverse Cholesterol Transport (RCT). RCT describes a mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam cell formation and the development of atherosclerosis. The aim of this review is to summarize the literature and to provide an updated overview of the effects of n-3 PUFAs on key players in RCT, including apoliprotein AI (apoA-I), ATP-binding cassette transporter A1 (ABCA1), ABCG1, apoE, scavenger receptor class B type I (SR-BI), cholesteryl ester transfer protein (CETP), low-density lipoprotein receptor (LDLr), cholesterol 7 alpha-hydroxylase (CYP7A1) and ABCG5/G8. Based on current knowledge, we conclude that n-3 PUFAs may beneficially affect RCT, mainly by influencing high-density lipoprotein (HDL) remodeling and by promoting hepatobiliary sterol excretion.

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Eicosapentaenoic acid membrane incorporation impairs ABCA1-dependent cholesterol efflux via a protein kinase A signaling pathway in primary human macrophages

Cited by 20 publications

References 68 publications

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Assessment of HDL Cholesterol Removal Capacity: Toward Clinical Application

The Role of Omega-3 Fatty Acids in Reverse Cholesterol Transport: A Review

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