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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Liver X Receptors (LXRs) regulate cholesterol homeostasis and immunity, making them promising drug targets for cardiovascular diseases.
• Synthetic LXR ligands show anti-atherogenic potential but cause adverse effects like increased lipogenesis, complicating therapeutic development.
• Dissecting beneficial from detrimental LXR ligand activities is crucial for effective cardiovascular disease treatment.

Purpose of the Study:

• To investigate how different Liver X Receptor (LXR) compounds induce distinct receptor conformations.
• To identify specific LXR regions responsible for anti-atherogenic versus lipogenic activities of ligands.
• To provide a basis for designing LXR ligands with improved therapeutic profiles.

Main Methods:

• Utilized hydrogen/deuterium exchange mass spectrometry (HDX-MS) to analyze LXR compound-induced conformational changes.
• Applied multivariate analysis to correlate structural changes with ligand activities.
• Examined the stabilization of LXRα and LXRβ active states and ABCA1 expression in response to various ligands.

Main Results:

• LXR compounds induced distinct receptor conformations, correlating with diverse functional responses.
• Lipogenic LXR ligands stabilized active states of both LXRα and LXRβ.
• Anti-atherogenic activity, specifically ABCA1 expression, was linked to ligand-induced stabilization of LXRα helix 3.

Conclusions:

• Ligand-induced stabilization of LXRα helix 3 is associated with beneficial anti-atherogenic effects.
• Avoiding interaction with LXR activation helix 12 while engaging helix 3 may lead to improved LXR ligand therapeutics.
• This research offers a structural basis for developing safer and more effective cardiovascular drugs targeting LXRs.