Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest

Z. X. Meng, J. Nie, J. J. Ling, J. X. Sun, Y. X. Zhu, L. Gao, J. H. Lv, D. Y. Zhu, Y. J. Sun, X. Han

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Aims/hypothesis Liver X receptors (LXRs) are important transcriptional regulators of lipid homeostasis and proliferation in several cell types. However, the roles of LXRs in pancreatic beta cells have not been fully established. The aim of this study was to investigate the effects of LXRs on pancreatic beta cell proliferation. Methods Gene expression was analysed using real-time RT-PCR. Transient transfection and reporter gene assays were used to determine the transcriptional activity of LXRs in pancreatic beta cells. Cell viability and proliferation were analysed using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), DNA fluorometric, BrdU labelling and [ 3H]thymidine incorporation assays. Cell cycle distribution was investigated by flow cytometry analysis. Adenovirus-based RNA interference was used to knockdown LXRα, LXRβ and p27 in MIN6 cells and mouse islets. Results We found that both Lxrα (also known as Nr1h3) and Lxrβ (also known as Nr1h2) were expressed and transactivated the LXR response element in HIT-T15 and MIN6 cells. Activation of LXRs dose-dependently inhibited pancreatic beta cell viability and proliferation. This was accompanied by beta cell cycle arrest at the G1 phase. Furthermore, LXR activation increased levels of the p27 protein by inhibiting its degradation. Knockdown of p27 reversed these effects of LXR activation on growth inhibition and cell cycle arrest. Conclusions/interpretation Our observations indicate that LXR activation inhibits pancreatic beta cell proliferation through cell cycle arrest. A well-known regulator of pancreatic beta cell cycle progression, p27, is upregulated and mediates the effects of LXRs on growth inhibition in beta cells. These observations suggest the involvement of aberrant activation of LXR in beta cell mass inadequacy, which is an important step in the development of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)125-135
Number of pages11
JournalDiabetologia
Volume52
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

Keywords

  • Beta cell
  • Cell cycle
  • Islet
  • LXR
  • P27
  • Proliferation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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