Activation of Liver X Receptors and Retinoid X Receptors Induces Growth Arrest and Apoptosis in Insulin-Secreting Cells

Abstract

Liver X receptors (LXRs) form functional heterodimers with the retinoid X receptors (RXRs) and regulate cholesterol, lipid, and glucose metabolism. We demonstrated previously that activation of LXR modulates insulin secretion in MIN6 cells and pancreatic islets. In this study we investigated the effects of the LXR agonist T0901317 and the RXR agonist 9-cis-retinoic acid (9cRA) on cell proliferation and apoptosis in MIN6 cells. Whereas T0901317 showed no effect on proliferation of MIN6 cells, combination of T0901317 with 9cRA inhibited cell proliferation. Flow cytometry analysis of cell cycle demonstrated that activation of LXR/RXR prevented MIN6 cells from G1 to G2 phase progression. Combination of T0901317 and 9cRA increased apoptosis rate and caspase-3/7 activity in MIN6 cells. Moreover, T0901317 or its combination with 9cRA significantly increased the cell susceptibility to free fatty acid- and cytokine-induced apoptosis. Treatment of MIN6 cells with LXR and RXR agonists produced a strong increase in expression of mothers against decapentaplegic homolog 3, a protein known to inhibit cell cycle G1/S phase progression and induce apoptosis. In isolated rat islets, the effect of palmitic acid on caspase-3/7 activity was increased with T0901317 alone and even more with the combination of T0901317 and 9cRA. Thus, activation of LXR/RXR signaling inhibits cell proliferation and induces apoptosis in pancreatic beta-cells.

The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro

“…Consequently, Choe and co-workers enhanced the adverse LXR effects when increasing the glucose concentrations to 31.2 mmol/l in their work [30]. Finally, we cannot rule out species-specific differences in the effects of LXRs, as murine islets or murine insulinoma cells were used by Choe et al [30] and Wente et al [40] whereas human pancreatic islets were used in our experiment. Such species differences may apply to pancreatic islets [27,37].…”

“…It has been established that LXR is important for maintaining normal beta cell function [39], but compelling evidence has shown that abnormal activation of LXR could also induce islet lipotoxicity [30,40]. A possible explanation may be the LXR agonist used (GW3965 in our study, T0901317 in the studies by Wente et al [40] and Choe et al [30]), as T0901317 has also been shown to be a potent pregnane X receptor ligand [41]. A second explanation may be the concentrations and/or exposure time used in the experiments, as we used both a relatively modest concentration and a relatively short incubation time (24 h).…”

Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

“…Three previous reports suggest that chronic activation of LXR in INS-1 cells and rat islets results in intra-islet lipid accumulation and eventual apoptosis (11)(12)(13). However, these adverse effects were observed with very high agonist concentrations (10 M) and only in the presence of high 9-cis-retinoic acid levels or prolonged exposure to high glucose.…”

“…These results suggest that activation of anaplerotic pathways contributes in part to LXR-induced increases in glucose-stimulated insulin secretion in human islets. (11)(12)(13). Whereas we observed an increase in the expression of several known LXR-targets as well as other genes known to be involved in lipogenesis, we sought to measure protein levels of key enzymes involved in lipogenesis under identical treatment conditions.…”

Chronic Activation of Liver X Receptor Induces β-Cell Apoptosis Through Hyperactivation of Lipogenesis

“…On the contrary, it appears that chronic LXR activation would induce ␤-cell dysfunction by inducing intracellular lipid and ROS accumulation. While we were preparing this manuscript, Wente et al (36) reported that activation of both LXR and RXR (retinoid X receptor) elevates ␤-cell apoptosis. From these results, it is possible to suggest that LXR can exert two different effects in ␤-cells depending on the duration of activation and/or other environmental conditions.…”