An update on non-steroidal liver X receptor agonists and their potential use in the treatment of atherosclerosis

Abstract

The liver X receptor (LXR)-α and -β isoforms are nuclear transcription factors that regulate the expression of a number of genes involved in lipid modulation. One key LXR target gene, which may offer therapeutic potential in the treatment of atherosclerosis, is the ATP-binding cassette transporter A1 (ABCA1) as it is involved in the process of reverse cholesterol transport. ABCA1 initiates the efflux of cholesterol from macrophages present in the atherosclerotic plaques of the arterial wall, where it is accepted by apolipoproteins such as apoA-1 and becomes high-density lipoprotein (HDL). HDL is then transported back to the liver for metabolism and excretion. A number of other genes are regulated by LXR function that may have positive or negative effects on atherosclerosis. Extrapolating the effect of individual gene regulation to an overall effect in humans, when all genes are modulated, is extremely difficult. This is further complicated by the fact that most preclinical work has been carried out in mice that differ quite significantly from humans in terms of lipid balance and metabolism. This review provides an update to the authors’ earlier patent review in this journal, which focused on the structural and biological data reported for LXR agonists in patent applications and associated literature. Various therapeutic indications have been reported for LXR agonists, but this review focuses solely on non-steroidal LXR agonists for the potential treatment of atherosclerosis.

Keywords::

• α and β isoforms
• atherosclerosis
• ATP-binding cassette transporter A1
• liver X receptor
• reverse cholesterol transport