Chromatin modification by lipids and lipoprotein components: an initiating event in atherogenesis? Silvio Zaina a , Kristina B.V. Døssing b , Marie Wickstro ¨ m Lindholm c and Gertrud Lund d Purpose of review This review examines recent evidence proposing that lipids and lipoproteins can act as nuclear factors regulating chromatin structure. These novel data broaden our understanding of the mechanisms by which lipoproteins can affect basic biological phenomena such as transcription, genome stability, and cell differentiation. Furthermore, they provide novel insights into the mechanisms of diseases associated with abnormal lipid levels, such as atherosclerosis and diabetes. Recent findings Data consistent with a role for lipids and lipoprotein components as nuclear factors, as well as initiators of cytoplasmic signalling events resulting in chromatin modification, have been published in the past year. In particular, new insights into the mechanisms of interaction between chromatin and small lipid molecules such as short- chain fatty acids and cholesterol, and endogenous lipid peroxidation products have been obtained. Furthermore, it has been shown that hyperlipidaemic lipoprotein profiles are associated with aberrant DNA methylation patterns at early stages of atherosclerosis in mice and in cultured human macrophages, suggesting that a rearrangement of DNA methylation patterns is among early molecular changes associated with atherogenesis. Summary The findings described here are prompting efforts to understand further how lipids and lipoprotein components can affect gene expression in normal and pathological cell behaviour through regulation of the chromatin structure. It is possible that novel candidate therapeutic tools will emerge from these studies. Keywords atherosclerosis, cancer, chromatin, DNA–lipid interaction, DNA methylation, epigenetics, histone, lipid, lipoprotein, nuclear lipid localization Curr Opin Lipidol 16:549–553. ß 2005 Lippincott Williams & Wilkins. a Institute of Medical Research, University of Guanajuato, Leon, Gto., Mexico, b Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark, c Experimental Cardiovascular Research, Department of Medicine, Lund University, UMAS, 205 02 Malmo ¨ , Sweden and d Department of Genetic Engineering, CINVESTAV, Irapuato, Gto., Mexico Correspondence to Silvio Zaina, Institute of Medical Research, University of Guanajuata, 20 de Enero no. 929, C.P. 37000, Leon, Gto., Mexico Tel: +52 477 714 3812; fax: +52 477 714 8354; e-mail: zailund@yahoo.com Sponsorship: This work was supported by the Danish Research Council (no. 22-02-0578), the Danish Heart Foundation (Hjerteforeningen, no. 03-1-2-30B-22061 and 04-10-B155-A236-22190), the Novo Nordisk Foundation (ref. 2003-11-28 and 2004-12-02), and Lundbeckfonden (no. 76/04) Current Opinion in Lipidology 2005, 16:549–553 ß 2005 Lippincott Williams & Wilkins 0957-9672 Introduction Lipids and lipoprotein components affect various aspects of cellular behaviour including survival and differen- tiation. According to established views, lipids and lipo- protein components elicit these responses by activating cell surface receptors or, upon internalization, by inter- acting with cytoplasmic regulatory factors that stimulate or repress specific signal transduction pathways. Depend- ing on the cell type and other concomitant factors, such signals may result in the specific modulation of transcrip- tion factor activity [1–3]. It is known that VLDL can induce smooth muscle cell proliferation [4], and that fatty acid-responsive elements are present in promoter regions, such as for genes involved in fibrinolysis [5]. In the case of cholesterol, the mechanisms by which sterol-responsive elements control gene expression have been intensely investigated [6,7]. However, recent evi- dence points to additional functions for lipids and lipo- protein components as regulators of chromatin structure. Chromatin consists of a basic repetitive complex called nucleosome, i.e. DNA wrapped around octamer com- plexes of duplicates of the histone proteins H2A, H2B, H3, and H4. Chromatin conformation is determined by various factors including DNA methylation and post- translational histone modifications (methylation, acetyla- tion, phosphorylation and ubiquitination) [8,9]. Generally, transcriptionally active (euchromatic) DNA regions are hypomethylated and are associated with hyperacetylated H3 and H4 together with hypermethylated lysine 4 and lysine 79 of H3, whereas silent chromatin (hetero- chromatin) contains hypermethylated DNA and deace- tylated and hypomethylated histones at corresponding residues. These mutation-independent, non-genetic but overall heritable (i.e. epigenetic) mechanisms of gene regulation are important determinants of cellular behaviour. For example, the establishment and main- tenance of specific DNA methylation patterns during gametogenesis is crucial for normal development, and 549