| Abstrakt: |
Novel agonists of the nuclear liver-X-receptor (LXR) are designed to treat metabolic disorders or cancer. The rationale to develop these new drugs is based on promising results with established LXR agonist like T0901317 and GW3965. LXRα and LXRβ are expressed in β-cells, and expression is increased by T0901317. The aim of the present study was to evaluate whether effects of these drugs on β-cell function are specific and reliably linked to LXR activation. T0901317 and GW3965, widely used as specific LXR agonists, show rapid, non-genomic effects on stimulus-secretion coupling of mouse pancreatic β-cells at low µM concentrations. T0901317 lowered the cytosolic Ca2+concentration, reduced or completely inhibited action potentials, and decreased insulin secretion. GW3965 exerted similar effects on insulin secretion. T0901317 affected the production of reactive oxygen species and ATP. The involvement of the classical nuclear LXRs in T0901317- and GW3965-mediated effects in β-cells could be ruled out using LXRα, LXRβ and double knockout mice. Our results strongly suggest that LXR agonists, that are considered to be specific for this receptor, interfere with mitochondrial metabolism and metabolism-independent processes in β-cells. Thus, it is indispensable to test novel LXR agonists accompanying to ongoing clinical trials for acute and chronic effects on cell function in cellular systems and/or animal models lacking classical LXRs. |
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