Approved LXR agonists exert unspecific effects on pancreatic β-cell function

Area of Science:

• Endocrinology
• Molecular Pharmacology
• Metabolic Disorders

Background:

• Novel liver-X-receptor (LXR) agonists are developed for metabolic disorders and cancer.
• Established agonists like T0901317 and GW3965 show promise.
• LXRα and LXRβ are expressed in pancreatic β-cells, with expression increased by T0901317.

Purpose of the Study:

• To evaluate if the effects of T0901317 and GW3965 on β-cell function are specific and reliably linked to LXR activation.
• To investigate the non-genomic mechanisms of LXR agonists in pancreatic β-cells.

Main Methods:

• Utilized mouse pancreatic β-cells and LXRα, LXRβ, and double knockout mouse models.
• Assessed cytosolic Ca2+ concentration, action potentials, insulin secretion, reactive oxygen species, and ATP production.
• Investigated rapid, non-genomic effects at low µM concentrations.

Main Results:

• T0901317 and GW3965 demonstrated rapid, non-genomic effects on β-cell stimulus-secretion coupling.
• T0901317 reduced Ca2+ levels, inhibited action potentials, and decreased insulin secretion, also affecting ROS and ATP.
• GW3965 similarly impacted insulin secretion.
• LXRα/β knockout mice ruled out classical LXR involvement in these observed effects.

Conclusions:

• LXR agonists, even those considered specific, interfere with mitochondrial and metabolism-independent processes in β-cells.
• It is crucial to test novel LXR agonists for acute and chronic effects on cell function in LXR-deficient systems.
• This comprehensive testing is essential for ongoing clinical trials involving LXR agonists.