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.

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.

Since the last International Bile Acid Meeting in Freiburg in 1996, considerable progress has been made in several areas of bile acid research. The different pathways of bile acid synthesis and their regulation have been further characterized. The molecular mechanisms for biliary secretion of bile acids have been elucidated and genetic defects of bile acid transport have been defined. Injurious as well as protective effects of different bile acids on the liver have been further studied. Finally, the beneficial effects of ursodeoxycholic acid in cholestatic liver diseases have been substantiated and the potential mechanisms of action have been explored. This book, the proceedings of the Falk Symposium No. 108 (XV International Bile Acid Meeting), held in Titisee, Germany, October 12-13, 1998, is dedicated to both basic and clinical aspects of bile acid research with a focus on bile acids and cholestasis.

This presentation describes various aspects of the regulation of tissue oxygenation, including the roles of the circulatory system, respiratory system, and blood, the carrier of oxygen within these components of the cardiorespiratory system. The respiratory system takes oxygen from the atmosphere and transports it by diffusion from the air in the alveoli to the blood flowing through the pulmonary capillaries. The cardiovascular system then moves the oxygenated blood from the heart to the microcirculation of the various organs by convection, where oxygen is released from hemoglobin in the red blood cells and moves to the parenchymal cells of each tissue by diffusion. Oxygen that has diffused into cells is then utilized in the mitochondria to produce adenosine triphosphate (ATP), the energy currency of all cells. The mitochondria are able to produce ATP until the oxygen tension or PO2 on the cell surface falls to a critical level of about 4–5 mm Hg. Thus, in order to meet the energetic needs of cells, it is important to maintain a continuous supply of oxygen to the mitochondria at or above the critical PO2 . In order to accomplish this desired outcome, the cardiorespiratory system, including the blood, must be capable of regulation to ensure survival of all tissues under a wide range of circumstances. The purpose of this presentation is to provide basic information about the operation and regulation of the cardiovascular and respiratory systems, as well as the properties of the blood and parenchymal cells, so that a fundamental understanding of the regulation of tissue oxygenation is achieved.

Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.

An overview of the supergene family made up of those nuclear hormone receptors which recognize thyroid and steroid hormones, vitamen D and retinoic acid and which are characterized by their ability to bind both ligands and the genes which respond to them.