Year-end Sale % OFF 
Abstract
Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain.
Highlights
The liver X receptors (LXRs) are Nuclear receptors (NRs) that act as oxysterol sensors, regulating genes involved in cholesterol and lipid metabolism
Some of these genes are the ATP-binding cassette (ABC) transporters A1 and G1, the sterol response element-binding protein-1c (SREBP-1c), the apolipoprotein E, phospholipid transport protein, cholesterol 7α-hydroxylase and several other genes involved in lipogenesis such as fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD) [25,26,27,28,29,30,31]
While the main focus of Liver X receptors (LXRs) ligand development in the past 10 years has been on therapeutically useful agonists, several naturally occurring antagonists have emerged in recent reports that demonstrated the ability to reduce triglycerides and improve fatty liver conditions, suggesting potential utility of LXR antagonists as therapeutic agents
Summary
Nuclear receptors (NRs) are one of the most abundant classes of transcriptional regulators in animals. The LXR/RXR complex binds to an LXR responsive element (LXRE) in the promoter region of target genes which consists of two direct repeats of hexameric nucleotides, AGGTCA, separated by four or one nucleotide(s) (DR4 or DR1) [10] It is through these target genes that LXR regulate various biological processes that are implicated in normal as well as pathological functions. While the mechanism of such trans-repression is not completely understood, the process is known to involve the inhibition of inflammatory responses to cytokines via blockade of the activity of the signal transducer and transcription activator nuclear factor NF-κB, and activator protein 1 that induce transcription of the proinflammatory genes COX2, MMP9, IL-6, MCP-1, iNOS, IL-1β [19,20,21,22,23,24]. Alterations in endogenous LXR activity is evidenced in many pathological conditions such as atherosclerosis, cancer, neurological disorders such as multiple sclerosis, Alzheimer disease and Parkinson disease, arthritis and skin diseases (Figure 1)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
