Liver X receptor agonists as a treatment for atherosclerosis

The liver X receptor (LXR)alpha and beta isoforms are members of the Type II nuclear receptor family that function as heterodimers with the retinoid X receptor (RXR). Upon agonist binding, the DNA binding domain (DBD) of LXR interacts with LXR response elements on target genes to initiate transcription. The ATP-binding cassette transporter ABCA1 is an LXR target gene, which is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to high-density lipoproteins (HDL) in the plasma. Decreased levels of HDL are pro-atherogenic and, as such, increasing RCT by LXR agonism is a potential therapeutic mechanism for the treatment of atherosclerosis. A number of other genes are upregulated by LXR activation and may have positive or negative effects on atherosclerosis. One such target gene is sterol regulatory element binding protein (SREBP)-1c, which is involved in the process of lipogenesis leading to increased levels of triglycerides, which are proatherogenic. This review focuses on the structural and biological data reported for LXR agonists that have been claimed for the treatment of atherosclerosis in patent applications and associated literature. A brief reference is made to patent applications claiming the use of LXR agonists for other therapeutic indications. The importance of the interactions made between LXR agonists and the LXR ligand binding domain (LBD), which have been highlighted in recent X-ray crystallographic publications are also discussed.