Non-steroidal LXR agonists; an emerging therapeutic strategy for the treatment of atherosclerosis

Recent Pat Cardiovasc Drug Discov. 2006 Jan;1(1):21-46. doi: 10.2174/157489006775244245.

Abstract

The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as obligate 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. A number of genes have been shown to be modulated by LXR function, including the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to high-density lipoproteins (HDL) in the plasma. Both homozygous and heterozygous mutations in ABCA1 result in conditions characterised by decreased levels of HDL and an earlier onset of atherosclerosis. A number of other genes are upregulated by LXR activation which would be expected to have either pro- or anti-atherogenic effects. One such target gene is sterol regulatory element binding protein-1c (SREBP-1c), which is involved in the process of lipogenesis leading to increased levels of triglycerides which are pro-atherogenic. The complexity of LXR responses, however, makes it difficult to extrapolate the 'positive' or 'negative' effects of each target gene in isolation to a conclusion as to the outcome in humans when all target genes are being modulated in concert. This review will cover the structural features and associated biological data of non-steroidal LXR modulators claimed for the treatment of cardiovascular disease, as well as highlighting preferred compounds where this information can be discerned. In addition to this patent information a précis of literature data relevant to the utility of specific compounds in the treatment of cardiovascular disease will be given where available.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • Acetyl-CoA Carboxylase / genetics
  • Animals
  • Atherosclerosis / drug therapy*
  • DNA-Binding Proteins / agonists*
  • Fatty Acid Synthases / genetics
  • Humans
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Osteopontin / genetics
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sulfonamides / therapeutic use
  • Thromboplastin / genetics

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • T0901317
  • Osteopontin
  • Thromboplastin
  • Fatty Acid Synthases
  • Acetyl-CoA Carboxylase