Targeting liver X receptors in human health: deadlock or promising trail?

Abstract

LXR are promising pharmacological targets because of the high potential to develop ligands owing to the variety of natural or synthetic agonists. Three aspects should be developed to select a LXR-ligand for treatment of human disease: bio-availability; isoform specificity; tissue specificity. This will allow the development of selective liver X modulators (SLiMs). The challenge is to overcome deleterious side effects to establish LXR as new pharmacological targets.

Role of Nuclear Receptors Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs) in the Human Placental Pathophysiology

“…Among them T0901317 (Schultz et al, 2000) and GW3965 (Collins et al, 2002), two nonsteroidal synthetic LXR agonists, are commonly used in experimental studies. T0901317, in contrast with GW3965, is not completely selective for LXR (Viennois et al, 2011).…”

“…Interestingly, even though both DNA and ligand-binding pockets share 80% identity, human and mouse LXR are shorter than LXR in their N-terminal domain (12 and 11 amino acids, respectively) and longer in the hinge region (23 and 18 amino acids, respectively). This fact could account for the lack of redundancy in vivo, even though both LXR isoforms bind similar DNA sequences and ligands in vitro (Viennois et al, 2011). LXR , , translation produces proteins of 447, 461 amino acids, respectively, with a molecular weight of 55 kDa for both (Michael et al, 2005).…”

“…The physiological LXR agonist ligands are oxysterols, oxidized metabolites of cholesterol. In mammals, there are two sources of plasmatic oxysterols, in vivo production by enzymatic or chemical pathways, and exogenous nutritional supply (Viennois et al, 2011). Natural activating oxysterols include 22(R) hydroxycholesterol in steroidogenic tissues, 24(S)-hydroxycholesterol in brain and plasma, 24(S),25-epoxycholesterol mainly found in the liver and 27-hydroxycholesterol in macrophages.…”

“…LXR was initially described as being highly expressed in a restricted subset of tissues known to play an important role in lipid metabolism such as liver, small intestine, kidney, spleen and adipose tissue whereas LXR was found to be ubiquitously expressed (Viennois et al, 2011).…”

Liver X receptors as potential targets for cancer therapeutics (Review)

“…LXRs exhibit the typical structure of the NR superfamily. LXRα and LXRβ harbor four distinct domains: i) An N-terminal activation domain (AF-1); ii) a DNA-binding domain with two zinc fingers; iii) a hinge domain that binds co-repressors in the absence of ligand; and iv) a C-terminal domain that contains a hydrophobic ligand-binding domain and a transactivation domain (11,12).…”