Regulation of HDL Genes: Transcriptional, Posttranscriptional, and Posttranslational

HDL regulation is exerted at multiple levels including regulation at the level of transcription initiation by transcription factors and signal transduction cascades; regulation at the posttranscriptional level by microRNAs and other noncoding RNAs which bind to the coding or noncoding regions of HDL genes regulating mRNA stability and translation; as well as regulation at the posttranslational level by protein modifications, intracellular trafficking, and degradation. The above mechanisms have drastic effects on several HDL-mediated processes including HDL biogenesis, remodeling, cholesterol efflux and uptake, as well as atheroprotective functions on the cells of the arterial wall. The emphasis is on mechanisms that operate in physiologically relevant tissues such as the liver (which accounts for 80 % of the total HDL-C levels in the plasma), the macrophages, the adrenals, and the endothelium. Transcription factors that have a significant impact on HDL regulation such as hormone nuclear receptors and hepatocyte nuclear factors are extensively discussed both in terms of gene promoter recognition and regulation but also in terms of their impact on plasma HDL levels as was revealed by knockout studies. Understanding the different modes of regulation of this complex lipoprotein may provide useful insights for the development of novel HDL-raising therapies that could be used to fight against atherosclerosis which is the underlying cause of coronary heart disease.

High-density lipoprotein • Regulation • Transcriptional • Posttranscriptional • Posttranslational • miRNAs • Protein stability • Hormone nuclear receptors • Hepatocyte nuclear factors • apoA-I • ABCA1 • ABCG1 • ABCG5 • ABCG8 • apoE • SR-BI • CETP

Regulation of Genes Involved in HDL Metabolism at the Transcriptional Level

A large body of work generated over the past four decades has revealed that eukaryotic gene transcription is a remarkably intricate biochemical process that is tightly regulated at many levels by the ordered assembly of multiprotein transcription initiation complexes to specific regulatory regions in the promoters of genes (Roeder 1998, 2005; Lemon and Tjian 2000). Despite the progress made, still limited knowledge regarding the details exists. It is believed that specificity in gene regulation is determined by the unique order of cis-acting regulatory regions which are recognized by sequence-specific DNA-binding transcription factors. Recent advances in gene regulation technologies including the powerful chromatin

immunoprecipitation assay have enabled the monitoring in real time of the ordered assembly and the disassembly of transcription factor complexes on the promoters and the enhancers of genes in response to extracellular or intracellular cues (Christova 2013; Rodriguez-Ubreva and Ballestar 2014). High-throughput sequencing technologies have revolutionized the fields of genomics, epigenomics, and transcriptomics and have provided novel insights into the transcription signatures of human diseases (Churko et al. 2013). Furthermore, using new powerful methodologies such as chromosome conformation capture (3C) and its derivatives, we are at a position to monitor dynamic intraand interchromosomal interactions that allow the optimal expression of genes at a given time and space (Gavrilov et al. 2009; Wei et al. 2013).

Transcription factors may be constitutively active in a cell or work in an inducible mode in response to various ligands and signal transduction pathways. The cross talk between different signaling pathways which orchestrate the cellular responses can be facilitated by the physical and functional interactions between transcription factors, and these interactions can be monitored by various methods both in vivo and in vitro. All known transcription factors are modular in nature and contain a DNA-binding domain and a transcriptional activation domain (Mitchell and Tjian 1989; Lemon and Tjian 2000). In addition, several factors contain a dimerization domain that permits them to form homodimers and/or heterodimers. A variety of nuclear receptors for steroids, thyroids, retinoids, etc. contain a ligand binding site. Via their transcription activation domains, transcription factors appear to facilitate the recruitment of the proteins of the coactivator complex and the basal transcription complex to the transcription initiation site of each gene and thus initiate transcription (Roeder 2005). Importantly, the activity of transcription factors can be modulated by drugs against diseases such as cancer and cardiovascular disease as exemplified by the drugs that activate or repress the hormone nuclear receptors (Gronemeyer et al. 2004).

It is beyond the scope of this chapter to provide a thorough review of the different mechanisms of transcriptional regulation of eukaryotic genes or to describe extensively the different classes of transcription factors, their structures, and their mode of regulation. We will only focus on those classes of transcription factors that have been shown to play key roles in the regulation of the genes involved in lipid and lipoprotein metabolism and more specifically on those involved in the metabolism of high-density lipoproteins (HDL) such as the hormone nuclear receptors.