Abstract
During the last three years there have been a plethora of publications on the liver X-activated receptors (LXRalpha, NR1H3, and LXRbeta, NR1H2), the farnesoid X-activated receptor (FXR, NR1H4), and the pregnane X receptor (PXR, NR1I2) and the role these nuclear receptors play in controlling cholesterol, bile acid, lipoprotein and drug metabolism. The current interest in these nuclear receptors is high, in part, because they appear to be promising therapeutic targets for new drugs that have the potential to control lipid homeostasis. In this review we emphasize i) the role of LXR in controlling many aspects of cholesterol and fatty acid metabolism, ii) the expanded role of FXR in regulating genes that control not only bile acid metabolism but also lipoprotein metabolism, and iii) the regulation of bile acid transport/metabolism in response to bile acid-activated PXR.
Highlights
CYP7A1 appears to be a central target for multiple nuclear receptors; CYP7A1 expression is repressed by both bile acid-activated pregnane X receptor (PXR) and farnesoid X-activated receptor (FXR), and induced by oxysterol-activated liver X-activated receptor (LXR)
The finding that administration of a cholesterol-rich diet to FXR null mice results in elevated levels of proathergenic lipoproteins [61] provides additional support for the idea that FXR has an important role in controlling normal plasma lipoprotein levels. It has been less than four years since natural ligands for LXR, FXR, and PXR were identified
The rapid increase in our understanding of these three receptors in this short time is a direct result of finding the “holy grail” and generating mice in which the genes encoding LXR, FXR, or PXR have been deleted
Summary
Nuclear receptors, which include both non-steroidal and steroid receptors, bind to DNA cis elements, known as hormone response elements (HREs) and activate transcription of target genes. Most non-steroidal receptors, such as LXR, FXR, and PXR (liver X-activated receptor, farnesoid X-activated receptor, and pregnane X receptor, respectively), bind DNA as heterodimers with the obligate partner 9-cis retinoic acid receptor ␣ (RXR␣, NR2B1) [1]. LXR, FXR, PXR, and RXR␣, like other members of this large superfamily of transcription factors, have a number of specific functional domains that usually include a poorly understood amino terminal transcriptional activation domain (AF-1), a DNA binding domain (DBD), a ligand binding domain (LBD), domains responsible for nuclear translocation and dimerization, and a transcriptional activation domain (AF-2) at the extreme carboxyl terminus (Fig. 1) [1, 3]. The role of the corepressor and coactivator proteins in controlling the condensed state of the DNA, via acetylation and deacetylation, has been reviewed recently, but is beyond the scope of the current article [4, 5]
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