Identification of a novel partial agonist of liver X receptor α (LXRα) via screening

Biochem Pharmacol. 2014 Dec 1;92(3):438-47. doi: 10.1016/j.bcp.2014.09.017. Epub 2014 Oct 17.

Abstract

Liver X receptor α (LXRα) plays an important role in the cholesterol metabolism process, and LXRα activation can reduce atherosclerosis. In the present study, using an LXRα-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXRα agonistic activity. IMB-170 significantly activated LXRα, with an EC50 value of 0.27μM. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with TO901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXRα. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXRα ligand-binding domain. In summary, IMB-170 is a novel partial LXRα agonist without the classical lipogenesis side effects, which could be used as a potential anti-atherosclerotic leading compound in the future.

Keywords: Atherosclerosis; Cholesterol efflux; LXRα; Partial agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apolipoproteins E / metabolism
  • Benzodioxoles / pharmacology*
  • Binding Sites
  • Caco-2 Cells / drug effects
  • Caco-2 Cells / metabolism
  • Cholesterol / metabolism
  • Drug Evaluation, Preclinical / methods
  • Gene Expression Regulation / drug effects
  • Hep G2 Cells / drug effects
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Lipid Metabolism / drug effects
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Lipoproteins / metabolism
  • Liver X Receptors
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins
  • Mice
  • Molecular Docking Simulation
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Quinazolinones / pharmacology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sulfonamides / pharmacology

Substances

  • ABCA1 protein, human
  • ABCG1 protein, human
  • ABCG5 protein, human
  • ABCG8 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • Benzodioxoles
  • Hydrocarbons, Fluorinated
  • IMB-170
  • Lipoproteins
  • Liver X Receptors
  • Membrane Proteins
  • Membrane Transport Proteins
  • NPC1L1 protein, human
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Quinazolinones
  • Recombinant Proteins
  • Sulfonamides
  • TO-901317
  • Cholesterol