Obesity-induced nucleosome release predicts poor cardio-metabolic health
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RESEARCH
Open Access
Obesity-induced nucleosome release predicts poor cardio-metabolic health Oriana Lo Re1,2†, Andrea Maugeri1,3†, Jana Hruskova1, Juraj Jakubik1, Jan Kucera4, Julie Bienertova-Vasku4,5, Jude A. Oben6, Lukas Kubala1,7, Adela Dvorakova7,8, Milan Ciz7,8 and Manlio Vinciguerra1,6*
Abstract Objective: While circulating nucleosome levels are high in obese mouse models, it is unknown where these nucleosomes originate from and whether they are a marker of cardio-metabolic health in humans. Here, we aimed to determine whether an association exists between circulating nucleosomes and the risk of developing obesity, metabolic syndrome (MetS) and/or a dysfunctional cardiovascular performance. Methods: We randomly selected 120 participants of the Kardiovize Brno 2030 study across three BMI strata: BMI 18–25, 25–30, and > 30. We assessed the association between circulating nucleosome levels and the risk of obesity, MetS, and poor cardiovascular health. We then cultured human neutrophils, adipocytes, and hepatoma cells to study nucleosome origins in a fat-rich environment. Results: Circulating nucleosome levels positively correlated with BMI (R = 0.602, p < 0.05), fatty liver index (R = 0.622, p < 0.05), left ventricular mass (R = 0.457, p < 0.05), and associated with MetS (p < 0.001) and poor cardiovascular health (p < 0.001). Incubating neutrophils with 1–10 μM free fatty acids triggered nucleosome production without concomitant cell death. Nucleosomes were not produced during pre-adipocyte differentiation or upon incubation of hepatic cells with palmitic acid. Conclusions: Neutrophils are a bona fide source of circulating nucleosomes in an obesogenic environment and in overweight/obese patients. High nucleosome levels are associated with MetS and cardiovascular performance, and might represent novel candidate biomarkers for cardio-metabolic health. Keywords: Liquid biopsy, Nucleosome, Epigenetics, Metabolic health, Cardiovascular disease
Introduction The nucleosome—the basic repeating unit of chromatin—was described > 40 years ago as DNA wrapped by an octameric core of histones [1]. Nucleosomes allow genome compaction and protection in the cell nuclei, and their composition and post-translational modifications regulate gene expression [2]. Cell-free DNA, histones, and nucleosomes are released into the blood stream upon cell death, both in health and disease. Interestingly, intact nucleosome levels in the circulation are elevated in several cancers and in acute conditions * Correspondence: [email protected] † Oriana Lo Re and Andrea Maugeri contributed equally to this work. 1 International Clinical Research Center, St Anne’s University Hospital, Brno, Czech Republic 6 Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, UK Full list of author information is available at the end of the article
such as stroke, trauma, and sepsis [3, 4]. Consequently, the use of circulating free DNA and nucleosomes from human plasma as a standard noninvasive diagn
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