Atherosclerotic coronary artery disease is still the leading cause of mortality in industrialised countries. This is largely related to the current tremendous increase of the prevalence of obesity, metabolic syndrome and diabetes. Therefore new strategies have to be developed for stopping such an epidemic situation. Drugs acting through the nuclear receptor LXR may offer an additional benefit or an alternative approach to current therapies since LXR receptors modulate not only the genes controlling the Reverse Cholesterol Transport (RCT) but also genes involved in pathways which are altered in metabolic diseases.

Originally identified as orphan members of the nuclear receptor superfamily, Liver X Receptors exist as two isoforms, LXRα and LXRβ. Oxysterols were identified as the putative physiological ligands for the LXRs, and additional studies have demonstrated that these receptors act as sensors for these cholesterol metabolites and are essential components of a physiological feedback loop regulating cholesterol metabolism and transport. LXR pathway may have also an important role in glucose metabolism since many reports now have shown that LXR-activation can be protective in genetic diabetes models in rodent, improve glucose tolerance and facilitate pancreas insulin secretion.

However the usefulness of LXRs as pharmacological targets has been questioned by the effect of systemic LXR-activation on the expression of hepatic lipogenic genes directly and via activation of hepatic sterol regulatory element-binding protein-1C (SREBP-1C) leading to hypertriglyceridemia and hepatic steatosis. Successful development of LXR-based therapeutics will therefore require methods to exploit the beneficial aspects of LXR-activation whereas avoiding these unwanted side effects.