Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands

Research output: Contribution to journalArticle

Authors

  • Anna Y. Belorusova
  • Emma Evertsson
  • Daniel Hovdal
  • Jenny Sandmark
  • Emma Bratt
  • Ingela Maxvall
  • Ira G. Schulman
  • Peter Åkerblad
  • Eva Lotte Lindstedt

External Institution(s)

  • AstraZeneca
  • Albireo

Details

Original languageEnglish (US)
Article number431
JournalCommunications Biology
Volume2
Issue number1
StatusPublished - Dec 1 2019
Peer-reviewedYes

Abstract

Liver X receptors (LXRs) are attractive drug targets for cardiovascular disease treatment due to their role in regulating cholesterol homeostasis and immunity. The anti-atherogenic properties of LXRs have prompted development of synthetic ligands, but these cause major adverse effects—such as increased lipogenesis—which are challenging to dissect from their beneficial activities. Here we show that LXR compounds displaying diverse functional responses in animal models induce distinct receptor conformations. Combination of hydrogen/deuterium exchange mass spectrometry and multivariate analysis allowed identification of LXR regions differentially correlating with anti-atherogenic and lipogenic activities of ligands. We show that lipogenic compounds stabilize active states of LXRα and LXRβ while the anti-atherogenic expression of the cholesterol transporter ABCA1 is associated with the ligand-induced stabilization of LXRα helix 3. Our data indicates that avoiding ligand interaction with the activation helix 12 while engaging helix 3 may provide directions for development of ligands with improved therapeutic profiles.

Citation formats

APA

Belorusova, A. Y., Evertsson, E., Hovdal, D., Sandmark, J., Bratt, E., Maxvall, I., ... Lindstedt, E. L. (2019). Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands. Communications Biology, 2(1), [431]. https://doi.org/10.1038/s42003-019-0675-0

Harvard

Belorusova, AY, Evertsson, E, Hovdal, D, Sandmark, J, Bratt, E, Maxvall, I, Schulman, IG, Åkerblad, P & Lindstedt, EL 2019, 'Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands', Communications Biology, vol. 2, no. 1, 431. https://doi.org/10.1038/s42003-019-0675-0