2013 Lizard + Iuliano Biochimie

Biochimie 95 (2013) 445–447 Contents lists available at SciVerse ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi Editorial Oxysterols and related sterols in chemistry, biology and medicine: A dynamic European field of investigation Oxysterols and related sterols, phytosterols and oxyphytosterols, have numerous activities and are suspected to play essential roles in the regulation of various biological processes and functions, and in the development of major diseases [1–3]. These molecules are structurally related to cholesterol, (3b)-cholest-5-en-3-ol, which is located in all membrane compartments and is the most prominent lipid in eukaryotic cells [4]. The cholesterol pool in the body results from dietary sources and de-novo synthesis in cells, except for the brain where the pool is entirely dependent on denovo synthesis [5]. Cholesterol functions in a variety of synthetic pathways, including those of bile acids, steroid hormones and vitamin D synthesis; it also largely affects membrane thermodynamics [6–8]. Most of these actions are associated with cholesterol oxidation, occurring either via enzymatic or non-enzymatic mechanisms [9,10]. The addition of oxygen into the cholesterol backbone creates a class of derivatives that are known as oxysterols and which are 27-carbon-atom cholesterol oxidation products. Depending on the position in the cholesterol backbone where the oxygen is inserted, the oxysterols have various functions. There are numerous cholesterol-metabolizing enzymes, many of which belong to the cytochrome P450 family, that are involved in the production of oxysterols. Oxysterols can also be formed in the absence of enzymatic catalysis by a pathway termed “autoxidation” produced by free radical species, i.e. the superoxide/hydrogen peroxide/hydroxyl radical system, and by non-radical reactive oxygen species such as singlet oxygen, HOCl, and ozone [10,11]. Oxysterols are known to exert a multitude of biological effects of potential pathophysiological relevance, which are mediated by biophysical effects on membranes and/or stereospecific interactions with proteins [2,3]. Oxysterols can be viewed as part of the cellular machinery that governs the integrity of the cell and function by acting at the level of signaling, as well as translational and post-translational gene regulation. Key targets for oxysterols include receptors such as the Hedgehog, transcription factors such as liver X receptors (LXRs), the sterol regulatory element binding proteins (SBREPs) or the estrogen receptor (ER), and other proteins involved in cholesterol homeostasis such as the HMG CoA reductase, the oxysterolbinding proteins (OSBP), the Nieman Pick disease proteins (NCP1, NCP2) [3,12,13]. Currently, the oxysterol area is expanding dramatically, and reveals more and more oxysterols of importance in biological systems. For instance, 7a,25-dihydroxycholesterol (also called 7a,25OHC or 5-cholesten-3b,7a,25-triol) has been identified as a potent 0300-9084/$ – see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.biochi.2013.01.012 and selective agonist of Epstein–Barr virus-induced gene 2 (EBI2, also known as GPR183) which is a G-protein-coupled receptor that is required for humoral immune responses [14]; 24-cholest5-ene-3b,7a-triol (a metabolic transformation product of 24S-OHcholesterol), and 7a-hydroxy-3-oxo-cholest-4-stenoic acid and 3b,7a-dihydroxy-5-cholestenoic acid (transformation products of 27-OH-cholesterol) impact on the control of brain cholesterol metabolism and with potential relevance in neurodegenerative diseases and aging [5]. European research, along with that of other countries but prevalently the US, has markedly contributed to the field of oxysterols, which can be traced back to 1940, with initial experiments at a chemical level and subsequent research into the biological and medical aspects of these compounds. Undoubtedly, EU scientists have played a central role in the field of oxysterols research. There are a number of specific problems in the field of oxysterols research. The field is expanding rapidly and there is a need to better include research on oxysterols in a translational research model. The problems in the field are inherent to the enormous complexity of the biology of oxysterols. The vast number of oxysterols showing biological effects, which continues to increase, necessitates advanced technology and very experienced scientists. Emerging problems in the field are the paucity of organic chemists with experience in the synthesis of oxysterols, most of which are not commercially available; the lack of uniformity of analytical chemistry procedures in oxysterol analysis with particular reference to mass spectrometry methods; the lack of tight integration among chemists, biologists and medical scientists to accomplish translational research in the area; the paucity of data on oxyphytosterols, oxidized analogs of phytosterols (which are mainly C-28 and C-29 carbon steroid alcohols), sterol compounds present in the diet, with an emerging role in biomedicine. EU research in the organic synthesis of oxysterols has been frontline in the past decades but is at risk of disappearing with the retirement of senior scientists who have made a substantial contribution. It is also important to note that the explosion of proteomics has to some extent compromised the area of mass spectrometry for lipid analysis. It is also important to underscore the inherently complicated problems in oxysterol analysis, linked to cholesterol autoxidation, resulting in abundant artefacts during sample processing. In 2010, we called upon European scientists working in the field to join a network aimed at promoting research in the area of 446 Editorial / Biochimie 95 (2013) 445–447 oxysterols. This resulted in the creation of The European Network on Oxysterols Research (ENOR), gathering scientists involved in chemistry, biology and medicine. Oxysterol research has intrinsic desirable benefits at the technological level. There is a need for implementing mass spectrometry tools to analyze on an “omic” basis the large number of oxysterols and for developing robust analytical procedures, validated by mass spectrometry methods, for clinical routine procedures. Such co-operation in this field is expected to foster the work of a wide community of scientists willing to develop and share different types of expertise, not only in biochemistry but also in various aspects of biomedicine (atherosclerosis, inflammation, metabolic diseases, cancer, neurodegeneration) and basic research (signaling, metabolism, regulation of gene expression) related to oxysterols. As a consequence, such a network is expected to produce a series of cascade effects in fundamental biochemical/biological knowledge, in understanding the roles of oxysterols in disease processes, and in developing new pharmacological tools and nutritional approaches. The articles of this special issue provide a cross section of current knowledge of oxysterols and related compounds. The diversity of information present in this special issue was the subject of the first ENOR symposium that was held in September 22–24, 2011 in Rome. This symposium successfully fostered collaborations between members of the network and favored the update of research results in their laboratories. The issue starts with an article from Dr Ingemar Björkhem (Stockholm, Sweden) – a pioneer in the area of oxysterols – entitled “Five Decades of Oxysterols”. The first part of the issue addresses the synthesis and analysis of oxysterols and oxyphytosterols. U. Diczfalusy (Stockholm, Sweden) illustrates the formation of 25-hydroxycholesterol. Y. Chen et al. (Swansea, UK) present an enzyme-assisted derivatisation procedure for the analysis of sterols by mass spectrometry. T. Vanmierlo et al. (Bonn, Germany) present a validated gas chromatography/ mass spectrometry (GC–MS) method for detecting trace amounts of oxyphytosterols in ex vivo and in vivo conditions. V. Cardenia et al. (Bologna, Italy) define a fast GC–MS method as a valid alternative for the analysis of cholesterol oxidation products. P. De Medina et al. (Toulouse, France) depict the production of anti-Dendrogenin A antibodies and the development of an enzyme-linked immunosorbent assay for detection of the natural steroidal alkaloid Dendrogenin A in human biological matrices. S. Matsyk and G. Schmitz (Regensburg, Germany) illustrate how GC coupled to triple quadrupole mass spectrometry offers new opportunities in the analysis of oxysterols and steroid hormones in humans. Y. O’Callaghan et al. (Cork, Ireland) expose the synthetic routes to campesterol and dihydrobrassicasterol oxides, and M. Baptissart et al. (Aubiere, France) expose the identification of new roles for bile acids. The topic of the second part points to the effects of oxysterols and related compounds. T. Nury et al. (Dijon, France) illustrate the biological activity of 4b- and 4a-hydroxycholesterol on oligodendrocytes (158N murine oligodendrocytes), the myelinsynthetizing cells. S. Meaney (Dublin, Ireland) presents the epigenetic regulation of oxysterol-forming genes. T. Vihervaara et al. (Helsinki, Finland) discuss how the molecular interactions of oxysterol-binding proteins reveal new functions in cell regulation. T. Mitic et al. (Edinburgh, UK) illustrate the role of 11b-hydroxysteroid-dehydrogenase type 1 in regulating 7oxysterols in atherosclerosis. S. Ducheix et al. (Toulouse, France) show that LXR acts as an oxysterol sensor and a master regulator of de novo fatty acid synthesis. Y. Hammoud and J.J. Mackrill (Cork, Ireland) develop the demonstration of how chronic oxysterol exposure alters the level and function of calcium signaling proteins in A7R5 rat aortic smooth muscle cells. The third part focuses on the role of oxysterols in cardiovascular, metabolic, neurodegenerative diseases, and cancer. J. Vaya (Kiryat Shmona, Israel) develops the design and use of novel exogenous markers for the characterization of human diseases associated with oxidative stress. G. Murdolo et al. (Perugia, Italy) present lipokines and oxysterols as novel adipose-derived lipid “hormones” linking adipose (dys)function and insulin resistance. V. Leoni and C. Caccia (Milan, Italy) depict a metabolic approach to study oxysterols and cholesterol metabolism in neurodegenerative diseases. S. Watterson et al. (Edinburgh, UK) show the involvement of oxysterols in inflammation and infection. M. Poirot and S. Silvente-Poirot (Toulouse, France) illustrate new roles of oxysterols in cancer, focusing on the role of cholesterol5,6-epoxides. The article from F. Biasi et al. (Turin, Italy) describing data on oxysterols and inflammatory bowel disease concludes this special issue. After around 70 years of research on oxysterols and related compounds, in light of the recent developments presented here, we hope that this special issue on ‘Oxysterols and related sterols in chemistry, biology and medicine’ will stimulate the interest of numerous scientists in order to elucidate the complex chemical, biochemical and biological properties of these compounds and to clarify their roles in diverse physiological and pathological processes. Acknowledgments We would like to thank all of our colleagues who agreed to contribute to this special issue of “Biochimie” on oxysterols, either as authors or referees. We hope that this issue reflects our current knowledge of the field and will stimulate further developments. We are particularly indebted to all ENOR members and participants of the Symposium for their encouraging and supporting enthusiasm. References [1] R.J. Morin, B. Hu, S.K. Peng, A. Sevanian, Cholesterol oxides and carcinogenesis, J. Clin. Lab. Anal. 5 (1991) 219–225. [2] S. Lordan, J.J. Mackrill, N.M. O’Brien, Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases, J. Nutr. Biochem. 20 (2009) 321–336. [3] A. Vejux, G. Lizard, Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis, Mol. Aspects Med. 30 (2009) 153–170. [4] R. Sato, Sterol metabolism and SREBP activation, Arch. Biochem. Biophys. 501 (2010) 177–181. [5] I. Björkhem, A. Cedazo-Minguez, V. Leoni, S. Meaney, Oxysterols and neurodegenerative diseases, Mol. Aspects Med. 30 (2009) 171–179. [6] V.M. Olkkonen, Oxysterol binding protein and its homologues: new regulatory factors involved in lipid metabolism, Curr. Opin. Lipidol. 15 (2004) 321–327. [7] E. Tissandié, Y. Guéguen, J.M. Lobaccaro, J. Aigueperse, M. Souidi, Vitamin D: metabolism, regulation and associated diseases, Med. Sci. (Paris) 22 (2006) 1095–1100. [8] S. Ducheix, J.M. Lobaccaro, P.G. Martin, H. Guillou, Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis, Chem. Phys. Lipids 164 (2011) 500–514. [9] N.B. Javitt, Oxysterols: novel biologic roles for the 21st century, Steroids 73 (2008) 149–157. [10] L. Iuliano, Pathways of cholesterol oxidation via non-enzymatic mechanisms, Chem. Phys. Lipids 164 (2011) 457–468. [11] L.L. Smith, Oxygen, oxysterols, ouabain, and ozone: a cautionary tale, Free Radic. Biol. Med. 37 (2004) 318–324. [12] D.J. Peet, B.A. Janowski, D.J. Mangelsdorf, The LXRs: a new class of oxysterol receptors, Curr. Opin. Genet. Dev. 8 (1998) 571–575. [13] S. Gill, R. Chow, A.J. Brown, Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised, Prog. Lipid Res. 47 (2008) 391–404. [14] S. Hannedouche, J. Zhang, T. Yi, W. Shen, D. Nguyen, J.P. Pereira, D. Guerini, B.U. Baumgarten, S. Roggo, B. Wen, R. Knochenmuss, S. Noël, F. Gessier, L.M. Kelly, M. Vanek, S. Laurent, I. Preuss, C. Miault, I. Christen, R. Karuna, Editorial / Biochimie 95 (2013) 445–447 W. Li, D.I. Koo, T. Suply, C. Schmedt, E.C. Peters, R. Falchetto, A. Katopodis, C. Spanka, M.O. Roy, M. Detheux, Y.A. Chen, P.G. Schultz, C.Y. Cho, K. Seuwen, J.G. Cyster, A.W. Sailer, Oxysterols direct immune cell migration via EBI2, Nature 475 (2011) 524–527. Luigi Iuliano1 Sapienza University of Rome, Department of Medico-Surgical Sciences and Biotechnologies, Laboratory of Vascular Biology and Mass Spectrometry, corso della Repubblica 79, 04100 Latina, Italy E-mail address: luigi.Iuliano@uniroma1.it 1 Tel.: þ39 0773 31757231; fax: þ39 06 62 29 1089. View publication stats 447 Gérard Lizard* Université de Bourgogne/INSERM/EA7270 Equipe BIO-peroxIL (Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique), Faculté des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France * Corresponding author. Laboratoire BIO-peroxIL (‘Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique’), Faculte des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France. Tel.: þ33 380 39 62 56; fax: þ33 380 39 62 50. E-mail address: Gerard.Lizard@u-bourgogne.fr