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.

Monocytes represent one of the major types of white blood cells in man which prevent infection by ingesting and killing invading pathogens and by releasing factors which stimulate and regulate lymphocytes. Monocytes "purify" the blood, removing immune complexes, mediating inflammatory responses, and initiating tissue repair. Human Monocytes represents an up-to-date, definitive account of this important cell. It covers the cells biochemical, immunological, and inflammatory functionsand its role in many diseases, including asthma, atherosclerosis, rheumatoid arthritis, and AIDS.

Liver X Receptors (LXRs), composed of LXR[alpha] and LXR[beta], are ligand activated nuclear receptors that are important regulators of cholesterol and lipid metabolism. LXRs control expression of genes involved in cholesterol efflux, fatty acid metabolism, and inflammation in tissues such as the liver and intestine. LXR[alpha] is highly expressed in liver resident macrophages, called Kupffer cells, which are involved in clearing pathogens from the portal circulation, as well as sensing tissue injury. During liver disease, such as nonalcoholic steatohepatitis (NASH), Kupffer cells are responsible for initiating a proinflammatory response program; therefore, I sought to understand the LXR-dependent responses modulating cholesterol accumulation and inflammation in Kupffer cells at both the steady state and during disease. I found a decreased expression of cholesterol efflux and inflammatory genes in Kupffer cells of mice lacking LXRs throughout all tissues but aimed to understand the function of LXRs intrinsic to Kupffer cells. Therefore, I studied a Lyz2 Cre and a novel Clec4f Kupffer cell specific Cre mouse lacking LXRs and saw an expansion of a new F4/80HiCd11bIntTim4Neg Kupffer cell population that is associated with fatty liver disease. Consequently, LXR activation may have beneficial properties, so pharmacological activation with a synthetic mimetic of the natural LXR ligand desmosterol was analyzed. Results suggest that this desmosterol mimetic dampens hepatic inflammation, lipid accumulation, and fibrosis, and may not only be targeting the liver, but also altering gene expression in the intestine as well. Thus, pharmacological activation of LXRs may act therapeutically in patients with fatty liver disease.

In this Handbook of Experimental Pharmacology on “High Density Lipoproteins – from biological understanding to clinical exploitation” contributing authors (members of COST Action BM0904/HDLnet) summarize in more than 20 chapters our current knowledge on the structure, function, metabolism and regulation of HDL in health and several diseases as well as the status of past and ongoing attempts of therapeutic exploitation. The book is of interest to researchers in academia and industry focusing on lipoprotein metabolism, cardiovascular diseases and immunology as well as clinical pharmacologists, cardiologists, diabetologists, nephrologists and other clinicians interested in metabolic or inflammatory diseases.