Liver X Receptors (LXRs) are nuclear hormone receptors that regulate key genes involved in cholesterol and lipid metabolism. As transcription factors, LXRs turn on the gene expression of ATP-binding cassette transporters (ABCs) which mediate cholesterol efflux from cells, such as macrophage foam cells. In addition, LXRs have the ability to down regulate pro-inflammatory genes. Therefore, LXRs have been extensively investigated as potential therapeutic targets for the treatment of conditions that result from altered cholesterol and lipid homeostasis as well as increased inflammation, such as atherosclerosis and Alzheimer's disease (AD). This latter is a neurodegenerative disorder that is associated with the deposition of brain amyloid plaques, constituted by insoluble A peptides. LXR activation has been shown to promote A clearance from the brain via the ABCA1-apolipoprotein E pathway and improve cognitive functions in rodent models of AD. The ability of LXRs to promote reverse cholesterol transport (RCT) and suppress inflammation has been characterized in both human and murine in vitro systems, but mostly in rodent in vivo systems. Although the LXR signaling pathway is mostly conserved across species, LXRs can also regulate their target genes in a species-, tissue- and isoform-specific fashion. Therefore the purpose of this work is to investigate the regulation of target genes by LXRs across species and identify, if any, differences that could aid us in understanding the role of LXR modulation in higher species, such as non-human primates. In the context of inflammation, the LXR genome landscape had only been investigated in murine macrophages. Therefore, we performed a genome-wide screen in human THP-1 macrophages. This led us to the identification of a novel LXR target gene, Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A), which is regulated in a species- and tissue-specific fashion, being restricted to human blood cells, with no induction by LXRs in mouse cellular systems. Next, we confirmed the LXR-mediated upregulation of ABCA1 and ApoE genes in Cynomolgus monkey brains, as this had never been investigated in higher species. In addition, we also characterized the LXR transcriptome in Cynomolgus brain by RNA-sequencing in order to identify potential novel LXR target genes. For the first time in higher species, we show Apolipoprotein AI upregulation in the brain of Cynomolgus monkey upon treatment with a synthetic LXR modulator.

With the invitation to edit this volume, I wanted to take the opportunity to assemble reviews on different aspects of circadian clocks and rhythms. Although most c- tributions in this volume focus on mammalian circadian clocks, the historical int- duction and comparative clocks section illustrate the importance of various other organisms in deciphering the mechanisms and principles of circadian biology. Circadian rhythms have been studied for centuries, but only recently, a mole- lar understanding of this process has emerged. This has taken research on circadian clocks from mystic phenomenology to a mechanistic level; chains of molecular events can describe phenomena with remarkable accuracy. Nevertheless, current models of the functioning of circadian clocks are still rudimentary. This is not due to the faultiness of discovered mechanisms, but due to the lack of undiscovered processes involved in contributing to circadian rhythmicity. We know for example, that the general circadian mechanism is not regulated equally in all tissues of m- mals. Hence, a lot still needs to be discovered to get a full understanding of cir- dian rhythms at the systems level. In this respect, technology has advanced at high speed in the last years and provided us with data illustrating the sheer complexity of regulation of physiological processes in organisms. To handle this information, computer aided integration of the results is of utmost importance in order to d- cover novel concepts that ultimately need to be tested experimentally.

The liver X receptors (LXRs) are members of the nuclear receptors superfamily of transcription factors. Multiple lines of evidence established LXRs as crucial regulators of metabolic homeostasis. Upon activation by cholesterol intermediates, LXRs induce the expression of a cluster of genes involved in cholesterol efflux, catabolism, and storage. In addition, activation of LXRs represses inflammatory signaling and enhances cellular survival against noxious stimuli. The diverse biologic roles of LXRs have made them attractive targets for pharmacologic manipulation. In this work, we utilized unbiased high-throughput genome-wide screens to identify novel LXR target genes.

In this second edition of Post-Genomic Cardiology, developing and new technologies such as translational genomics, next generation sequencing (NGS), bioinformatics, and systems biology in molecular cardiology are assessed in light of their therapeutic potential. As new methods of mutation screening emerge, both for the genome and for the “epigenome, comprehensive understanding of the many mutations that underlie cardiovascular diseases and adverse drug reactions is within our reach. This book, written by respected cardiologist José Marín-García, features discussion on the Hap-Map: the largest international effort to date aiming to define the differences between our individual genomes. This unique reference further reviews and investigates genome sequences from our evolutionary relatives that could help us decipher the signals of genes, and offers a comprehensive and critical evaluation of regulatory elements from the complicated network of the background DNA. Offers updated discussion of cutting-edge molecular techniques including new genomic sequencing / NGS / Hap-Map / bioinformatics / systems biology approaches Analyzes mitochondria dynamics and their role in cardiac dysfunction, up-to-date analysis of cardio-protection, and cardio-metabolic syndrome Presents recent translational studies, gene therapy, transplantation of stem cells, and pharmacological treatments in CVDs

Biochemistry of Lipids: Lipoproteins and Membranes, Volume Six, contains concise chapters that cover a wide spectrum of topics in the field of lipid biochemistry and cell biology. It provides an important bridge between broad-based biochemistry textbooks and more technical research publications, offering cohesive, foundational information. It is a valuable tool for advanced graduate students and researchers who are interested in exploring lipid biology in more detail, and includes overviews of lipid biology in both prokaryotes and eukaryotes, while also providing fundamental background on the subsequent descriptions of fatty acid synthesis, desaturation and elongation, and the pathways that lead the synthesis of complex phospholipids, sphingolipids, and their structural variants. Also covered are sections on how bioactive lipids are involved in cell signaling with an emphasis on disease implications and pathological consequences. Serves as a general reference book for scientists studying lipids, lipoproteins and membranes and as an advanced and up-to-date textbook for teachers and students who are familiar with the basic concepts of lipid biochemistry References from current literature will be included in each chapter to facilitate more in-depth study Key concepts are supported by figures and models to improve reader understanding Chapters provide historical perspective and current analysis of each topic

This timely volume provides a comprehensive overview of glucocorticoids and their role in regulating many aspects of physiology and their use in the treatment of disease. The book is broken into four sections that begin by giving a general introduction to glucocorticoids and a brief history of the field. The second section will discuss the effects of glucocorticoids on metabolism, while the third section will cover the effects of glucocorticoids on key tissues. The final section will discuss general topics, such as animal models in glucocorticoid research and clinical implications of glucocorticoid research. Featuring chapters from leaders in the field, this volume will be of interest to both researchers and clinicians.